2021/10/22 更新

写真a

マキノ ヒロフミ
槇野 博史
MAKINO Hirofumi
所属
本部 学長
職名
学長
ホームページ
外部リンク

学位

  • 医学博士 ( 岡山大学 )

研究キーワード

  • Endocrinology and Metabolism Science

  • Nephrology

  • 腎臓内科学

  • 内分泌・代謝学

研究分野

  • ライフサイエンス / 腎臓内科学

  • ライフサイエンス / 膠原病、アレルギー内科学

  • ライフサイエンス / 代謝、内分泌学

学歴

  • 岡山大学   Faculty of Medicine  

    - 1975年

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  • 岡山大学   医学部   医学科

    - 1975年

      詳細を見る

    国名: 日本国

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経歴

  • Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2011年 - 2014年

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  • 岡山大学医歯薬学総合研究科 教授

    2011年 - 2014年

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  • - 岡山大学 理事

    2011年

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  • - Executive director,Okayama University

    2011年

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  • - Hospital Director,University Hospital of Medicine and Dentistry,Okayama University

    2011年

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  • - 岡山大学岡山大学病院 病院長

    2011年

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  • 岡山大学医歯薬学総合研究科 教授

    2004年 - 2011年

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  • Professor,Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,Okayama University

    2004年 - 2011年

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▼全件表示

所属学協会

▼全件表示

委員歴

  • 日本リウマチ学会   理事、評議員、指導医、専門医  

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    団体区分:学協会

    日本リウマチ学会

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  • 日本臨床リウマチ学会   評議員  

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    団体区分:学協会

    日本臨床リウマチ学会

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  • 日本内科学会   評議員、指導医、認定医  

      詳細を見る

    団体区分:学協会

    日本内科学会

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  • 日本糖尿病合併症学会   評議員,幹事  

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    団体区分:学協会

    日本糖尿病合併症学会

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  • 日本心血管内分泌代謝学会   評議員  

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    団体区分:学協会

    日本心血管内分泌代謝学会

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  • 日本内分泌学会   代議員、内分泌代謝特例指導医  

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    団体区分:学協会

    日本内分泌学会

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  • 日本病態栄養学会   理事、評議員  

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    団体区分:学協会

    日本病態栄養学会

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  • 日本高血圧学会   評議員  

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    団体区分:学協会

    日本高血圧学会

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  • 日本予防医学会   理事  

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    団体区分:学協会

    日本予防医学会

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  • 日本腎臓学会   評議員、指導医、専門医  

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    団体区分:学協会

    日本腎臓学会

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  • 日本老年医学会   代議員  

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    団体区分:学協会

    日本老年医学会

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  • 日本糖尿病・肥満動物学会   幹事、評議員  

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    団体区分:学協会

    日本糖尿病・肥満動物学会

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  • 日本糖尿病学会   指導医、評議員、専門医  

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    団体区分:学協会

    日本糖尿病学会

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  • 日本臨床分子形態学会   評議員  

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    団体区分:学協会

    日本臨床分子形態学会

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  • 日本透折医学会   理事、評議員、指導医、専門医  

      詳細を見る

    団体区分:学協会

    日本透折医学会

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▼全件表示

 

書籍等出版物

  • かかりつけ医/非腎臓専門医と腎臓専門医の協力を促進する慢性腎臓病患者の 重症化予防のための診療システムの有用性を検討する研究.

    厚生労働科学研究費補助金 腎疾患対策研究事業 戦略研究(腎疾患重症化予防のための戦略研究) 平成23年度総括・分担研究報告書  2012年 

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  • 難治性血管炎に関する調査研究.

    厚生労働科学研究費補助金難治性疾患克服研究事業 難治性血管炎に関する調査研究 平成23年度総括・分担研究報告書  2012年 

     詳細を見る

  • 厚生労働科学研究費補助金難治性疾患克服研究事業 難治性血管炎に関する調査研究平成22年度総括・分担研究報告書

    難治性血管炎に関する調査研究平成22年度総括・分担研究報告書  2011年 

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  • 平成20年度岡山医学会賞(砂田賞)受賞論文 副腎皮質細胞におけるアルドステロンブレイクスルー現象とBMP-6の関与.

    岡山医学会  2010年 

     詳細を見る

  • 第53回日本腎臓学会学術総会.

    先端医学社  2010年 

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  • 厚生労働科学研究費補助金糖尿病戦略等研究事業 平成20年度総括研究報告書

    富山大学  2009年 

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  • 厚生労働科学研究費補助金難治性疾患克服研究事業 難治性血管炎に関す調査研究 平成20年度総括・分担研究報告書

    岡山大学  2009年 

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  • 高血圧ナビゲーター 第2版

    メディカルレビュー社  2008年 

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  • 厚生労働科学研究費補助金 難治性疾患克服研究事業 進行性腎障害に関する調査研究 平成19年度 総括・分担研究報告書

    2008年 

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  • 厚生労働科学研究費補助金 難治性疾患克服研究事業 進行性腎障害に関する調査研究 平成19年度 総括・分担研究報告書

    2008年 

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  • 厚生労働科学研究費補助金 難治性疾患克服研究事業 進行性腎障害に関する調査研究 平成17〜19年度 総合研究報告書

    2008年 

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  • 厚生労働科学研究費補助金 難治性疾患克服研究事業 進行性腎障害に関する調査研究 平成19年度 総括・分担研究報告書

    2008年 

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  • 平成19年度厚生労働科学研究費補助金再生医療等研究事業 総括・分担研究報告書

    2008年 

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  • 平成17年〜19年度厚生労働科学研究費補助金再生医療等研究事業 総合研究報告書

    2008年 

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  • 心腎連関を識る―心から腎を、腎から心を診る―

    文光堂  2008年 

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  • 腎・尿路系コア・カリキュラムテキスト

    文光堂  2008年 

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  • EBM腎臓の治療2008-2009

    中外医学社  2008年 

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  • メタボリックシンドロームリスク管理のための健診・保健指導ガイドライン

    南山堂  2008年 

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  • 慢性腎臓病(CKD)診療ガイダンス

    メジカルヴュー社  2008年 

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  • 慢性腎臓病(CKD)診療ガイダンス

    メジカルヴュー社  2008年 

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  • 今日の病態栄養療法(改訂第2版)

    南江堂  2008年 

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  • 薬局 病気と薬 パーフェクトBOOK

    南山堂  2008年 

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  • 心腎相関の病態理解と診療

    羊土社  2008年 

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  • Annual Review 糖尿病・代謝・内分泌

    中外医学社  2008年 

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  • Annual Review 腎臓

    中外医学社  2008年 

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  • 糖尿病学の進歩(第41集)

    診断と治療社  2007年 

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  • 平成18年度 厚生労働科学研究 循環器疾患等生活習慣病対策総合研究 研究成果発表会報告書

    財団法人 循環器病研究振興財団  2007年 

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  • 厚生労働科学研究費補助金難治性疾患克服研究事業 進行性腎障害に関する調査研究 平成18年度 総括・分担研究報告書

    2007年 

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  • 厚生労働科学研究費補助金 ヒトゲノム・再生医療等研究事業 平成18年度総括・分担研究報告書

    2007年 

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  • 新しい糖尿病学と透析医療2007年6月

    日本メディカルセンター  2007年 

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  • 第二回分冊Ⅰ アクロメガリフォーラム記録集 MEDICAL Publisher

    2007年 

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  • 第9版 内科学

    朝倉書店  2007年 

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  • 腎不全治療マニュアル

    財団法人 日本透析医会  2007年 

     詳細を見る

  • メタボリックシンドロームと循環器合併症

    中外医学社  2007年 

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  • 厚生労働科学研究費補助金(難治性疾患克服研究事業)分担研究報告書 難治性血管炎に関する調査研究 平成18年度総括・分担研究報告書

    2007年 

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  • New専門医を目指すケース・メソッド・アプローチ5

    日本医事新報社  2007年 

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  • 腎疾患・透析 最新の治療2008-2010

    南江堂  2007年 

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  • 腎疾患・透析 最新の治療2008-2010

    南江堂  2007年 

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  • 透析ナーシングQ&A(No.18)

    総合医学社  2007年 

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  • ジョスリン糖尿病学 第2版

    2007年 

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  • 腎臓病を外来で診る

    診断と治療社  2007年 

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  • 糖尿病性腎症 基礎と臨床の最前線

    中外医学社  2007年 

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  • 臨床検査ガイド2007年〜2008年

    文光堂  2007年 

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  • 週刊朝日増刊号 病気にならない健康食2007

    朝日新聞社  2007年 

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  • 糖尿病最新の治療2007-2009

    南江堂  2007年 

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  • Annual Review 2006 腎臓

    中外医学社  2006年 

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  • 上原財団生命科学財団研究報告集 vol.20

    2006年 

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  • 厚生労働科学研究費補助金(難治性疾患克服研究事業) 難治性血管炎に関する調査研究 平成17年度分担研究報告書

    2006年 

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  • 厚生労働省科学研究費補助金 ヒトゲノム・再生医療等研究事業平成17年度 総括・分担研究報告書

    2006年 

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  • 看護のための最新医学講座 糖尿病と合併症 第8巻

    中山書店  2006年 

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  • 厚生労働省科学研究費補助金 ヒトゲノム・再生医療等研究事業平成17年度 総括・分担研究報告書

    2006年 

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  • 腹膜透析

    2006年 

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  • 機能性食品共同研究事業 平成17年度文部科学省補助事業成果報告書

    2006年 

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  • 厚生労働科学研究費補助金(難治性疾患克服研究事業)進行性腎障害に関する調査研究 平成17年度総括・分担研究報告書

    2006年 

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  • 厚生労働科学研究費補助金(難治性疾患克服研究事業)進行性腎障害に関する調査研究 平成17年度総括・分担研究報告書

    2006年 

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  • 動脈硬化診療 今後の展望 動脈硬化診療マニュアル

    南江堂  2006年 

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  • Annual Review 2006 腎臓

    中外医学社  2005年 

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  • 二次性腎疾患 改定第2版

    南江堂  2004年 

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  • 免疫疾患の合併症とその治療法に関する研究 平成15年度総括研究報告

    2004年 

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  • 糖尿病合併症診かた・考えかた

    メディカルレビュー社  2004年 

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  • 糖尿病UP-DATE 腎セミナー19

    医歯薬出版株式会社  2004年 

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  • 免疫疾患の合併症とその治療法に関する研究 平成15年度総括研究報告

    2004年 

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  • 免疫疾患の合併症とその治療法に関する研究 平成15年度総括研究報告

    2004年 

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  • 免疫疾患の合併症とその治療法に関する研究 平成15年度総括研究報告

    2004年 

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  • 免疫アレルギー疾患予防・治療研究事業 研究報告

    厚生労働省  2004年 

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  • 平成15年度厚生労働科学研究費補助金「免疫アレルギー疾患予防・治療研究事業研究報告

    2004年 

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  • 平成15年度厚生労働科学研究費補助金「免疫アレルギー疾患予防・治療研究事業研究報告

    2004年 

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  • 日経メディカル9月号

    2004年 

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  • 「腎とフリーラジカル」第7集

    東京医学社  2004年 

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  • 腎臓ナビゲーター

    メディカルレビュー社  2004年 

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  • 腎臓ナビゲーター

    メディカルレビュー社  2004年 

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  • 進行性腎障害に関する調査研究 平成15年度 総括・分担研究報告書

    2004年 

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  • 進行性腎障害に関する調査研究 平成14年度 総括・分担研究報告書

    2004年 

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  • からだの科学[増刊] 糖尿病2005

    2004年 

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  • Medical Tribune 第4部

    2004年 

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  • AGEs研究の最前線-糖化蛋白関連疾患研究の現状-

    メディカルレビュー社  2004年 

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  • 腎不全とともに歩んで-透析医療の常識・非常識

    日本メディカルセンター  2004年 

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  • Annual Review 腎臓2003

    2003年 

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  • 臨床に直結する腎疾患治療のエビデンス

    文光堂,東京  2003年 

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  • 臨床に直結する腎疾患治療のエビデンス

    文光堂,東京  2003年 

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  • 名医が答える医療相談

    朝日新聞社,東京  2003年 

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  • 平成14年度厚生労働科学研究費補助金免疫アレルギー疾患予防・治療研究事業研究報告会抄録集

    2003年 

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  • 平成14年度厚生労働科学研究費補助金 免疫アレルギー疾患予防・治療研究事業報告会抄録集

    2003年 

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  • 分子腎臓病学実験操作法―腎臓病の病態解明に向けて

    文光堂,東京  2003年 

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  • 内科学Ⅱ第2版

    文江堂,東京  2003年 

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  • 糖尿病診療のコツと落とし穴

    中山書店,東京  2003年 

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  • 腎不全と高血圧

    フジメディカル出版,大阪  2003年 

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  • 新しい診断と治療のABC11 慢性腎不全

    最新医学社,大阪  2003年 

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  • 実地医家のための糖尿病合併症 診断・治療ハンドブック

    エンゼビアジャパン,東京  2003年 

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  • 治療薬ガイド 2003-2004

    文光堂,東京  2003年 

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  • 今日の病態栄養療法

    南光堂,東京  2003年 

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  • 厚生科学研究費補助金 免疫アレルギー疾患予防治療研究事業 免疫疾患の合併症とその治療法に関する研究 平成15年度総括研究報告書

    2003年 

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  • 厚生科学研究費補助金 免疫アレルギー疾患予防治療研究事業 免疫疾患の合併症とその治療法に関する研究 平成14年度総括研究報告書

    2003年 

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  • 医学のあゆみ 腎疾患state of arts 2003-2005

    医歯薬出版株,東京  2003年 

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  • 医学のあゆみ 腎疾患state of arts 2003-2005

    医歯薬出版株,東京  2003年 

     詳細を見る

  • ファーマナビゲーターCa拮抗薬編

    メディカルレビュー社,東京  2003年 

     詳細を見る

  • ダイナミックメディシン6

    西村書店,新潟  2003年 

     詳細を見る

  • Contribution of Nephrology: Renal Fibrosis

    Karger,Basel  2003年 

     詳細を見る

  • 老年医学

    朝倉書店,東京  2003年 

     詳細を見る

  • KIDNEY DISEASES 腎臓疾患(第3版)

    日本医事新報社,東京  2002年 

     詳細を見る

  • 膠原病・血管炎の腎障害Up to Date

    東京医学社,東京  2002年 

     詳細を見る

  • 病気の形態学

    国際企画,東京  2002年 

     詳細を見る

  • 標準腎臓病学

    医学書院,東京  2002年 

     詳細を見る

  • 標準腎臓病学

    医学書院,東京  2002年 

     詳細を見る

  • 標準腎臓病学

    医学書院,東京  2002年 

     詳細を見る

  • 糖尿病合併症治療のイノベーションーARL(アルドース還元酵素阻害薬)―

    医薬ジャーナル社,東京  2002年 

     詳細を見る

  • 第29回かなえ医学助成金受賞者研究業績集

    2002年 

     詳細を見る

  • 専門医のための腎臓病学

    医学書院,東京  2002年 

     詳細を見る

  • 腎臓病―専門医にきく最新の臨床

    中外医学社,東京  2002年 

     詳細を見る

  • 今日の診断指針 第5版

    医学書院,東京  2002年 

     詳細を見る

  • 解離性大動脈瘤と冠動脈狭窄のマルチスライスCT画像診断

    2002年 

     詳細を見る

  • わかる糖尿病性腎症―診断から透析療法までー

    診断と治療社,東京  2002年 

     詳細を見る

  • わかる糖尿病性腎症

    診断と治療社,東京  2002年 

     詳細を見る

  • わかる糖尿病性腎症

    診断と治療社,東京  2002年 

     詳細を見る

  • わかる糖尿病性腎症

    診断と治療社,東京  2002年 

     詳細を見る

  • プロスタサイクリンの多様性と今後の展望

    メディカルレビュー社,大阪  2002年 

     詳細を見る

  • 看護のための最新医学講座. 糖尿病と合併症

    中山書店  2001年 

     詳細を見る

  • 研修医ノート?医の基本

    診断と治療社  2001年 

     詳細を見る

  • 研修医ノート?医の基本

    診断と治療社  2001年 

     詳細を見る

  • 研修医ノート?医の基本

    診断と治療社  2001年 

     詳細を見る

  • Contrib Neohrol:Type-2 Diabetic Nephropathy in Japan. From Bench to Bedside.

    Karger  2001年 

     詳細を見る

  • 臨床検査診断マニュアル

    永井書店、  2001年 

     詳細を見る

  • 糖尿病第44巻

    日本糖尿病学会  2001年 

     詳細を見る

  • 糖尿病専門医研修ガイドブック

    診断と治療社  2001年 

     詳細を見る

  • 糖尿病学の進歩2001.

    診断と治療社  2001年 

     詳細を見る

  • 糖尿病のとらえかた

    文光堂  2001年 

     詳細を見る

  • 糖尿病Up・Date17 糖尿病の診断から治療へのベストアプローチ

    医歯薬出版(株)  2001年 

     詳細を見る

  • 第13回実地医家腎疾患研究会記録集

    実地医家腎疾患研究会  2001年 

     詳細を見る

  • 腎臓病の最新医療

    先端医療技術研究所  2001年 

     詳細を見る

  • 腎臓病の最新医療

    先端医療技術研究所  2001年 

     詳細を見る

  • 腎と透析 第51巻臨時増刊号2001

    東京医学社  2001年 

     詳細を見る

  • 腎と透析 第51巻臨時増刊号2001

    東京医学社  2001年 

     詳細を見る

  • 厚生科学研究費補助金 健康科学総合研究事業 平成12年度総括・分担研究報告書

    岡山大学  2001年 

     詳細を見る

  • 愛媛医学 20(4)

    愛媛大学  2001年 

     詳細を見る

  • メディカルスタッフのための糖尿病性腎症のアプローチ

    文江堂  2001年 

     詳細を見る

  • Role of Macrophages in the Pathogenesis of Diabetic Nephropathy Type-2 Diabetic Nephropathy in Japan. From Bench to Bedside. Contrib

    Basel, Karger  2001年 

     詳細を見る

  • プラクティカル内科シリーズ10 腎炎とネフローゼ?診断へのアプローチと治療戦略

    南江堂  2000年 

     詳細を見る

  • 免疫系,免疫不全(分担)

    「透析療法における合併症」,医薬ジャーナル社 

     詳細を見る

  • 維持透析患者の病態生理(分担)「免疫能」

    透析入門,秀潤社 

     詳細を見る

  • 糖尿病におけるミトコンドリア機能異常と糖尿病合併症進展への関与

    上原記念生命科学財団研究報告集 

     詳細を見る

  • 糸球体基底膜の透過性制御

    腎疾患-State of arts,医歯葉出版(株) 

     詳細を見る

  • 日本人における内臓脂肪蓄積型肥満の客観的・科学的病態評価法に関する研究:

    平成11年度厚生科学研究費補助金、健康科学 総合研究事業研究報告書 

     詳細を見る

  • 健康づくりセンターを活用した生活習慣病予防のための地域連携システムの開発:

    平成11年度厚生科学研究費補助金、健康科学総合研究事業研究報告書 

     詳細を見る

  • RPGNの早期発見・早期治療に関する研究-指針・治療法の試案-

    厚生省特定疾患進行性腎障害調査研究班平成10年度研究業績 

     詳細を見る

  • 腎疾患と接着分子

    接着分子-分子機構と医学への応用,中外医学社 

     詳細を見る

  • 糖尿病性慢性合併症の発生機序へのアプローチ、プロテオグリカン代謝異常の立場から

    糖尿病学の進歩''93第27集,診断と治療社 

     詳細を見る

  • 慢性血液透析患者の難治性皮膚掻痒症に対する脂肪乳剤の効果

    日本透析療法学会誌 

     詳細を見る

  • Overview/槇野博史

    プラクティカル内科シリーズ10 腎炎とネフローゼー診断へのアプロ-チと治療戦略(槙野博史編) 南江堂、東京 

     詳細を見る

  • 糖尿病・肥満患者と口腔疾患.

    厚生科学研究「口腔保健と全身的な健康状態の関係」 

     詳細を見る

  • 腎炎ネフローゼ 1.ループス腎炎の発症機序-疾患感受性 遺伝子の検討:

    Annual Review腎臓2000.中外医学社、東京 

     詳細を見る

  • 膠原病および類縁疾患に伴う腎障害

    外来診療のすべて,メジカルビュー社 

     詳細を見る

  • 糖尿病を合併した高血圧の治療を教えてください(共)

    高血圧診療Q&A 日本医学出版 東京 

     詳細を見る

  • 20.腎不全患者における薬剤投与法(共)

    内科学 [(]G0002[)] 文光堂 東京 

     詳細を見る

  • Overview

    プラクティカル内科シリーズ10 腎炎とネフローゼ-診断へのアプローチと治療戦略.槇野編、南江堂、東京 

     詳細を見る

  • Part5糖尿病・代謝異常を伴った高血圧とA(]G0002[)受容体拮抗薬、6.糖尿病性腎症とA(]G0002[)受容体拮抗薬

    A(]G0002[)受容体拮抗薬のすべて(第2版)、先端医学社、東京 

     詳細を見る

  • ACE阻害薬+A(]G0002[)受容体拮抗薬:

    高血圧ナビゲーター.荻原・猿田・他監修、メディカルレビュー社、東京 

     詳細を見る

  • ループス腎炎の治療

    知っておきたい膠原病の新たな診療.安倍・槇野編著、医書出版部、東京 

     詳細を見る

  • ジギタリス製剤とループ利尿薬不整脈

    この薬の多剤併用副作用.松田編、医歯薬出版、東京 

     詳細を見る

  • (]G0003[).糖尿病 4c.合併症-腎症:

    Annual Review内分泌、代謝2000.中外医学社、東京 

     詳細を見る

  • 全身請疾患と腎障害

    最新内科学大系 内科臨床リファレンスブロク疾患編(]G0002[) 中山書店 

     詳細を見る

  • ヒトの糸球体と病変

    人体組織学,朝倉書店 

     詳細を見る

  • 透析療法導入基準および透析方法の選択

    プラクティカル内科シリーズ3 糖尿病性腎症 南江堂 

     詳細を見る

  • 6.糖尿病合併症に関する最近の知見 2.糖尿病性腎症進展へのアンギオテンシン(]G0002[)受容体の関与(共)

    分子糖尿病学の進歩-基礎から臨床まで-金原出版、東京 

     詳細を見る

  • 21.腎・尿路系の疾患 3)膠原病・血管炎の腎障害(共)

    第7版内科学 朝倉書店 東京 

     詳細を見る

  • ケース15 糖尿病性腎症 血圧の変動に苦慮した糖尿病透析患者の1例(共)

    症例に学ぶ糖尿病合併症専門医のみるポイント46 メディカルビュー社 東京 

     詳細を見る

  • 浮腫およびネフローゼ症候群の治療法(共)

    糖尿病性腎症のベッドサイドマニュアル 中山書店 東京 

     詳細を見る

  • 間質・尿細管 発症進展における接着分子の役割(共)

    Annual Review腎臓1999 中外医学社 東京 

     詳細を見る

  • 糖尿病 合併症-腎症(共)

    Annual Review内分泌、代謝1999 中外医学社 東京 

     詳細を見る

  • 間質性腎炎

    疾患別最新処方 改訂第3版 メディカルビュー 

     詳細を見る

  • 腎疾患 尿細管間質性腎炎

    今日の診断指針第4版,医学書院 

     詳細を見る

  • 全身性疾患と腎障害,膠原病および近縁疾患

    内科学,朝倉書店 

     詳細を見る

  • ループス腎炎の治療と管理

    腎疾患診療のジレンマ 金芳堂 

     詳細を見る

  • 30の大学病院による診断と治療シリーズ・岡山大学第3内科血尿・蛋白尿・排尿障害の診断と治療

    血尿・蛋白尿・排尿障害の診断と治療 真興交易医書出版部 

     詳細を見る

  • 腎臓と高血圧 3.アンギオテンシン(]G0002[)受容体

    Annual Review腎臓1998 中外医学社 

     詳細を見る

  • 腎疾患 膠原病による腎疾患

    1998今日の治療指針 私はこう治療している 医学書院 

     詳細を見る

  • (]G1038[)痒症の対策 脂肪乳剤の適応とその効果

    透析フロンティア,メディカルレビュー社 

     詳細を見る

  • 細胞膜表面蛋白とその可溶性成分からみた血液透析療法の生体適合性

    ハイパフォ-マンスメンブレン''98,東京医学社 

     詳細を見る

  • 血液透析が単球膜表面CD14発現量と血清中可溶性CD14濃度に与える影響

    ハイパフォーマンスメンブレン''98,東京医学社 

     詳細を見る

  • 妊娠と腎

    EBM現代内科学,金芳堂 

     詳細を見る

  • 活性酸素により誘導されるメサンギウム習胞の細胞死

    腎とフリーラジカル第3集,東京医学社 

     詳細を見る

  • 活性酸素による腎糸球体プロテオグリカンの変化(分担)

    「腎とフリーラジカル 第2集」 東京医学社 

     詳細を見る

  • 腎疾患 腎糸球体の透過性制御

    医学のあゆみ(腎疾患-state of arts) 

     詳細を見る

  • 腎糸球体の構造とその異常

    「糖尿病血管合併症の診断と治療」メデイカルビュー社 

     詳細を見る

  • 糖尿病性腎症の形態学的アプローチ

    「分子糖尿病学の進歩」金原出版 

     詳細を見る

  • 腎疾患

    「細胞外マトリックス-臨床医学への応用」メディカルレビュー社 

     詳細を見る

  • アンチセンス療法

    「Annual Review腎臓1996」, 中外医学社 

     詳細を見る

  • 全身疾患に伴う関節症, 透析患者に見られる関節症

    最新内科学大系 

     詳細を見る

  • 慢性関節リウマチ, その他の膠原病に伴う腎障害

    最新内科学大系 

     詳細を見る

  • Relevance of proteoglycans in glomerular matrix pathology.

    Nephrology, Springer-Verlag 

     詳細を見る

  • 基底膜型ヘパラン硫酸プロテオグリカンに対する抗体の応用

    新生化学実験講座,糖質IIプロテオグリカンとグリコサミノグリカン東京化学同人 

     詳細を見る

  • Role of apoptosis in the progression of glomerulo-sclerosis.

    「Progression of Chronic Renal Diseases」Karger, Basel 

     詳細を見る

  • Inhibition of mesangial cell proliferation and matrix expansion by antisense oligonucleotides

    「Recent Advances in Molecular Nephrology」Kohko-do 

     詳細を見る

  • Applecation of electron microscopic autoradiography in the study of glomerular diseases using antibody against heparan sulfate proteoglycan.

    Electron Microscopic Radioautography, Shinshu Univ. Press 

     詳細を見る

  • Extracellular matrix in glomerular disease.

    Molecular and biological approach to glomerular injuries. Nishimura Smith-Gordon 

     詳細を見る

  • Relevance of proteoglycans in glomerular matrix pathology.

    Nephrology, Springer-Verlag 

     詳細を見る

  • Role of apoptosis in the progression of glomerulo-sclerosis.

    「Progression of Chronic Renal Diseases」Karger, Basel 

     詳細を見る

  • Inhibition of mesangial cell proliferation and matrix expansion by antisense oligonucleotides

    「Recent Advances in Molecular Nephrology」Kohko-do 

     詳細を見る

  • Applecation of electron microscopic autoradiography in the study of glomerular diseases using antibody against heparan sulfate proteoglycan.

    Electron Microscopic Radioautography, Shinshu Univ. Press 

     詳細を見る

  • Extracellular matrix in glomerular disease.

    Molecular and biological approach to glomerular injuries. Nishimura Smith-Gordon 

     詳細を見る

▼全件表示

MISC

  • Involvement of bone morphogenetic protein activity in somatostatin actions on ovarian steroidogenesis

    Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Kanako Ogura-Ochi, Tomoko Miyoshi, Kishio Toma, Masaya Takeda, Hirofumi Makino

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   134   67 - 74   2013年3月

     詳細を見る

    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Somatostatin is expressed in the hypothalamus, pancreas and gastrointestinal tracts and it inhibits the secretion of various hormones in vivo. In the rodent ovary, somatostatin receptor (SSTR) subtypes 2 and 5 are expressed in granulosa cells and oocytes. Somatostatin analogs have been clinically used for treatment of endocrine tumors. For this purpose, relatively high-dose or long-term treatments of somatostatin analogs are necessary; however, the direct and continuous impact of somatostatin analogs on gonadal functions has yet to be elucidated. In the present study, we investigated the effects of somatostatin analogs (octreotide and pasireotide) on ovarian steroidogenesis by rat primary granulosa cell culture. The expression levels of SSTR2 and SSTR5 in granulosa cells were upregulated by FSH treatment. Treatment with somatostatin analogs decreased FSH-induced estradiol production with reduction in aromatase mRNA expression, while the treatment also suppressed FSH-induced progesterone production with reduction of mRNAs levels of StAR, P450scc and 3 beta HSD2 in granulosa cells. This trend was also observed in a granulosa/oocyte co-culture condition. The effect of pasireotide was more potent than that of octreotide. FSH-induced synthesis of steroids and cAMP was also suppressed by somatostatin analog treatment. Notably, pretreatment with a BMP-binding protein, noggin reversed the suppressive effects of somatostatin analogs on progesterone and cAMP production, suggesting that the endogenous BMP system is functionally involved in the SSTR effects in granulosa cells. Treatment with BMP-2, -4, -6 and -7 decreased the mRNA expression of inhibitory Smads6 and 7, leading to enhancement of BMP actions detected by Id-1 transcription in granulosa cells. Collectively, the results revealed that SSTR activation modulates ovarian steroidogenesis by upregulating endogenous BMP activity in growing follicles. (c) 2012 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2012.10.018

    Web of Science

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  • The serum vaspin levels are reduced in Japanese chronic hemodialysis patients

    Junko Inoue, Jun Wada, Sanae Teshigawara, Kazuyuki Hida, Atsuko Nakatsuka, Yuji Takatori, Shoichirou Kojo, Shigeru Akagi, Kazushi Nakao, Nobuyuki Miyatake, John F. McDonald, Hirofumi Makino

    BMC NEPHROLOGY   13   63 - 163   2012年12月

     詳細を見る

    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified in genetically obese rats that correlates with insulin resistance and obesity in humans. Recently, we found that 7% of the Japanese population with the minor allele sequence (A) of rs77060950 exhibit higher levels of serum vaspin. We therefore evaluated the serum vaspin levels in Japanese chronic hemodialysis patients.
    Methods: Healthy Japanese control volunteers (control; n = 95, 49.9 +/- 6.91 years) and Japanese patients undergoing hemodialysis therapy (HD; n = 138, 51.4 +/- 10.5 years) were enrolled in this study, and serum samples were subjected to the human vaspin RIA system.
    Results: The measurement of the serum vaspin levels demonstrated that a fraction of control subjects (n = 5) and HD patients (n = 11) exhibited much higher levels (> 10 ng/ml; Vaspin(High) group), while the rest of the population exhibited lower levels (< 3 ng/ml; Vaspin(Low) group). By comparing the patients in the Vaspin(Low) group, the serum vaspin levels were found to be significantly higher in the control subjects (0.87 +/- 0.24 ng/ml) than in the HD patients (0.32 +/- 0.15 ng/ml) (p < 0.0001). In the stepwise regression analyses, the serum creatinine and triglyceride levels were found to be independently and significantly associated with the vaspin concentrations in all subjects.
    Conclusions: The creatinine levels are negatively correlated with the serum vaspin levels and were significantly reduced in the Japanese HD patients in the Vaspin(Low) group.

    DOI: 10.1186/1471-2369-13-163

    Web of Science

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  • Losartan/Hydrochlorothiazide Combination Therapy Surpasses High-dose Angiotensin Receptor Blocker in the Reduction of Morning Home Blood Pressure in Patients with Morning Hypertension

    Yoshihisa Hanayama, Haruhito Adam Uchida, Yoshio Nakamura, Hirofumi Makino

    ACTA MEDICA OKAYAMA   66 ( 6 )   449 - 459   2012年12月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Angiotensin receptor blockers (ARBs) are the first-line antihypertensive agents. In clinical practice, it is often difficult to achieve the recommended blood pressure level by ARBs in their ordinal dosages alone. This study examined the practical efficacy of a combination therapy of ARB with thiazide diuretics for lowering morning home blood pressure (MHBP) in comparison to high-dose ARB therapy in patients with morning hypertension administered an ordinal dosage of ARB. This study was performed in a prospective, randomized, open-labeled and blind-endpoint fashion. Patients were considered to have morning hypertension when their self-measured systolic MHBPs were 135 mmHg or higher, irrespective of their diastolic MHBP and office blood pressures (OBPs). Forty-eight outpatients with morning hypertension receiving the ordinal dosage of ARB were given either losartan/hydrochlorothiazide (n = 26) or high-dose ARB (n = 22) in place of their previously prescribed ARB. No change in any medication was permitted during this period. Decreases of both systolic and diastolic MHBP after 3 months of treatment were significantly greater in the losartan/hydrochlorothiazide group than in the high-dose ARB group (p < 0.05, respectively). The ratio of adverse events was somewhat high (23.1% in the losartan/hydrochlorothiazide group, 9.1% in the high-dose ARB group, respectively). However, there were no significant differences in any particular adverse event between groups. This study suggested losartan/hydrochlorothiazide might be superior to high-dose ARB for reducing morning home blood pressure.

    DOI: 10.18926/AMO/49041

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  • Renal disease in the elderly and the very elderly Japanese: analysis of the Japan Renal Biopsy Registry (J-RBR)

    Hitoshi Yokoyama, Hitoshi Sugiyama, Hiroshi Sato, Takashi Taguchi, Michio Nagata, Seiichi Matsuo, Hirofumi Makino, Tsuyoshi Watanabe, Takao Saito, Yutaka Kiyohara, Shinichi Nishi, Hiroyuki Iida, Kunio Morozumi, Atsushi Fukatsu, Tamaki Sasaki, Kazuhiko Tsuruya, Yukimasa Kohda, Makoto Higuchi, Hideyasu Kiyomoto, Shin Goto, Motoshi Hattori, Hiroshi Hataya, Shoji Kagami, Norishige Yoshikawa, Yuichiro Fukasawa, Yoshihiko Ueda, Hiroshi Kitamura, Akira Shimizu, Kazumasa Oka, Naoki Nakagawa, Takafumi Ito, Shunya Uchida, Kengo Furuichi, Izaya Nakaya, Satoshi Umemura, Keiju Hiromura, Mitsuhiro Yoshimura, Nobuhito Hirawa, Takashi Shigematsu, Masafumi Fukagawa, Makoto Hiramatsu, Yoshio Terada, Osamu Uemura, Tetsuya Kawata, Akira Matsunaga, Aki Kuroki, Yasukiyo Mori, Koji Mitsuiki, Haruyoshi Yoshida

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   16 ( 6 )   903 - 920   2012年12月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Data regarding renal disease in the elderly (age a parts per thousand yen65 years old) and very elderly (age a parts per thousand yen80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy.
    From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed.
    The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life.
    Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

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  • Case of emphysematous cholecystitis in a patient with type 2 diabetes mellitus associated with schizophrenia

    Ayu Ogawa, Kenichi Shikata, Haruhito Adam Uchida, Susumu Shinoura, Naosuke Yokomichi, Daisuke Ogawa, Chicage Sato-Horiguchi, Takahito Yagi, Jun Wada, Hirofumi Makino

    JOURNAL OF DIABETES INVESTIGATION   3 ( 6 )   534 - 535   2012年12月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    Emphysematous cholecystitis is a rare, but life-threatening, form of acute cholecystitis caused by gas-forming organisms in the gallbladder. A 73-year-old male patient with type 2 diabetes mellitus complicated with neuropathy associated with schizophrenia was admitted to Okayama University Hospital, Okayama, Japan, because of a high fever and general malaise. On the fourth hospital day, despite normal liver function tests and little abdominal pain, his abdominal computed tomography showed huge gas formation in the gallbladder lumen along with a dilated gallbladder with a thickened wall, consistent with emphysematous cholecystitis. The patient underwent an emergency open cholecystectomy. Few abdominal symptoms appeared because of the hyposensitivity to pain caused by not only diabetic neuropathy, but also antipsychotic agents the patient was taking for schizophrenia. Emphysematous cholecystitis should be taken into consideration for the differential diagnosis of high fever in diabetic patients with schizophrenia, irrespective of the level of liver function tests and clinical symptoms. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00232. x, 2012)

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  • Right hypoplastic kidney

    Ayu Ogawa, Shinji Kitamura, Kazunori Nakayama, Hitoshi Sugiyama, Naoya Morisada, Kazumoto Iijima, Hirofumi Makino

    KIDNEY INTERNATIONAL   82 ( 9 )   1037 - 1037   2012年11月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    DOI: 10.1038/ki.2012.201

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  • Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex

    Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Chikage Sato Horiguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

    DIABETES   61 ( 11 )   2823 - 2832   2012年11月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 2012

    DOI: 10.2337/db12-0232

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  • Activation of Liver X Receptor Inhibits Osteopontin and Ameliorates Diabetic Nephropathy

    Hiromi Tachibana, Daisuke Ogawa, Yuichi Matsushita, Dennis Bruemmer, Jun Wada, Sanae Teshigawara, Jun Eguchi, Chikage Sato-Horiguchi, Haruhito Adam Uchida, Kenichi Shikata, Hirofumi Makino

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   23 ( 11 )   1835 - 1846   2012年11月

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    記述言語:英語   出版者・発行元:AMER SOC NEPHROLOGY  

    Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin-induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy.

    DOI: 10.1681/ASN.2012010022

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  • Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex

    Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Chikage Sato Horiguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

    DIABETES   61 ( 11 )   2823 - 2832   2012年11月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions. Diabetes 61:2823-2832, 2012

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  • REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME IN A YOUNG ADULT PATIENT RECEIVING PERITONEAL DIALYSIS

    Ayu Ogawa, Hitoshi Sugiyama, Kazunori Nakayama, Hiroshi Morinaga, Shigeru Akagi, Hirofumi Makino

    PERITONEAL DIALYSIS INTERNATIONAL   32 ( 6 )   587 - 589   2012年11月

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    記述言語:英語   出版者・発行元:MULTIMED INC  

    DOI: 10.3747/pdi.2011.00055

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  • Mizoribine, tacrolimus, and corticosteroid combination therapy successfully induces remission in patients with lupus nephritis

    Hidetoshi Kagawa, Tsutomu Hiromasa, Takayuki Hara, Ayako Takaki, Ryutaro Yamanaka, Ken-ei Sada, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   16 ( 5 )   760 - 766   2012年10月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.
    We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.
    All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.
    This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.

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  • Phenotypic change of macrophages in the progression of diabetic nephropathy; sialoadhesin-positive activated macrophages are increased in diabetic kidney

    Ryo Nagase, Nobuo Kajitani, Kenichi Shikata, Daisuke Ogawa, Ryo Kodera, Shinichi Okada, Yuichi Kido, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   16 ( 5 )   739 - 748   2012年10月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Inflammatory process is involved in pathogenesis of diabetic nephropathy, although the activation and phenotypic change of macrophages in diabetic kidney has remained unclear. Sialoadhesin is a macrophage adhesion molecule containing 17 extracellular immunoglobulin-like domains, and is an I-type lectin which binds to sialic acid ligands expressed on hematopoietic cells. The aim of this study is to clarify the activation and phenotypic change of macrophages in the progression of diabetic nephropathy.
    We examined the expression of surface markers for pan-macrophages, resident macrophages, sialoadhesin, major histocompatibility complex class II and alpha-smooth muscle actin in the glomeruli of diabetic rats using immunohistochemistry at 0, 1, 4, 12, and 24 weeks after induction of diabetes by streptozotocin. Expression of type IV collagen and the change of mesangial matrix area were also measured. The mechanism for up-regulated expression of sialoadhesin on macrophages was evaluated in vitro.
    The number of macrophages was increased in diabetic glomeruli at 1 month after induction of diabetes and the increased number was maintained until 6 months. On the other hand, sialoadhesin-positive macrophages were increased during the late stage of diabetes concomitantly with the increase of alpha-smooth muscle actin-positive mesangial cells, mesangial matrix area and type IV collagen. Gene expression of sialoadhesin was induced by stimulation with interleukin (IL)-1 beta and tumor necrosis factor-alpha but not with IL-4, transforming growth factor-beta and high glucose in cultured human macrophages.
    The present findings suggest that sialoadhesin-positive macrophages may contribute to the progression of diabetic nephropathy.

    DOI: 10.1007/s10157-012-0625-3

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  • Peritoneovenous shunting for refractory ascites results in worsening of nephrotic syndrome

    Akinobu Takaki, Yohei Maeshima, Takahito Yagi, Akihiro Katayama, Norikazu Hinamoto, Shigeru Akagi, Hitoshi Sugiyama, Takeshi Tomoda, Yoshiaki Iwasaki, Tetsuya Yasunaka, Fusao Ikeda, Yasuhiro Miyake, Haruhiko Kobashi, Atsushi Hirano, Hirofumi Makino, Kazuhide Yamamoto

    HEPATOLOGY RESEARCH   42 ( 10 )   1048 - 1053   2012年10月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    Peritoneovenous shunt (PVS) is accepted as a treatment for refractory ascites due to liver cirrhosis. Infection is a well-known complication of shunting. However, the effects of PVS in terms of complications for renal disease are unclear. We encountered a case involving a 52-year-old man with alcoholic liver cirrhosis and complications of nephrotic syndrome that were worsened by PVS. He received PVS for refractory ascites due to alcoholic liver cirrhosis before coming to our hospital for evaluation for liver transplantation. Nephrotic syndrome was then identified due to cirrhosis-related membranoproliferative glomerulonephritis (MPGN). Prednisolone was administrated at 60 mg/day for MPGN. On day 5, he showed grade IV hepatic encephalopathy (West Haven criteria). Tapering prednisolone and intestinal cleansing with lactulose treatment improved hepatic encephalopathy, but hyperammonemia persisted and the PVS was removed. After shunt removal, urinary protein levels decreased from 46 g/day to 0.30.5 g/day and ammonia levels decreased. PVS may increase the excretion of urinary protein and increase ammonia levels in patients with complications of glomerulonephritis.

    DOI: 10.1111/j.1872-034X.2012.01012.x

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  • An in vivo role of bone morphogenetic protein-6 in aldosterone production by rat adrenal gland

    Yoshinori Matsumoto, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Mariko Takano-Narazaki, Tomoko Miyoshi, Eri Nakamura, Kanako Ogura-Ochi, Masaya Takeda, Hirofumi Makino

    JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY   132 ( 1-2 )   8 - 14   2012年10月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. We previously reported the presence of a functional BMP system including BMP-6 in human adrenocortical cells. BMP-6 contributes to Ang II-induced aldosterone production by activating Smad signaling, in which endogenous BMP-6 action is negatively controlled by Ang II in vitro. In the present study, we examined the in vivo role of BMP-6 in regulation of aldosterone by neutralizing endogenous BMP-6 in rats treated with immunization against BMP-6. Three-week-old male rats were actively immunized with rat mature BMP-6 antigen conjugated with keyhole limpet hemocyanin (KLH). The immunization treatment had no effect on bilateral adrenal weight or its ratio to body weight. Urinary aldosterone excretion was time-dependently increased during the 8-week observation period in the control group. Of note, the level of urinary aldosterone excretion in BMP-6-KLH-immunized rats was significantly reduced compared to that in the control group, suggesting that endogenous BMP-6 contributes to the induction of aldosterone production in vivo. Moreover, the level of urinary aldosterone/creatinine after 8-week treatment was significantly lowered by treatment with BMP-6-KLH. In contrast, with chronic Ang II treatment, urinary aldosterone and creatinine-corrected values at 8 weeks were not significantly different between the two groups, suggesting that the effects of BMP-6-KLH were impaired under the condition of chronic treatment with Ang II. The mRNA levels of Cyp1162, but not those of Star, P450scc and 3 beta hsd2, were significantly decreased in adrenal tissues isolated from BMP-6-KLH-immunized rats after 8-week treatment. Furthermore, the ratio of plasma aldosterone level to corticosterone was significantly decreased by immunization with BMP-6-KLH. Collectively, the results indicate that endogenous BMP-6 is functionally linked to aldosterone synthesis by the zona glomerulosa in the adrenal cortex in vivo. (C) 2012 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jsbmb.2012.04.004

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  • Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice

    Daisuke Kawai, Akinobu Takaki, Atsuko Nakatsuka, Jun Wada, Naofumi Tamaki, Tetsuya Yasunaka, Kazuko Koike, Ryuichiro Tsuzaki, Kazuyuki Matsumoto, Yasuhiro Miyake, Hidenori Shiraha, Manabu Morita, Hirofumi Makino, Kazuhide Yamamoto

    HEPATOLOGY   56 ( 3 )   912 - 921   2012年9月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-cholinedeficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet + control water (CW group); (2) MCD diet + hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesisrelated genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling (TUNEL)positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912921)

    DOI: 10.1002/hep.25782

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  • The frequency of Fabry disease with the E66Q variant in the α-galactosidase A gene in Japanese dialysis patients:a case report and a literature review.

    Kikumoto Y, Sugiyama H, Morinaga H, Inoue T, Takiue K, Kitagawa M, Saito D, Takatori Y, Kinomura S, Akagi S, Sada K, Nakao K, Maeshima Y, Kitayama H, Makino H

    Clinical Nephrology   78 ( 3 )   224 - 229   2012年9月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.5414/CN107097

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  • Spred-2 deficiency exacerbates acetaminophen-induced hepatotoxicity in mice

    Hiroshi Wakabayashi, Toshihiro Ito, Soichiro Fushimi, Yuki Nakashima, Jyunya Itakura, Liu Qiuying, Min Min Win, Sun Cuiming, Cao Chen, Miwa Sato, Megumi Mino, Tetsuya Ogino, Hirofumi Makino, Akihiko Yoshimura, Akihiro Matsukawa

    CLINICAL IMMUNOLOGY   144 ( 3 )   272 - 282   2012年9月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    MAPKs are involved in acetaminophen (APAP)-hepatotoxicity, but the regulatory mechanism remains unknown. Here, we explored the role of Spred-2 that negatively regulates Ras/ERK pathway in APAP-hepatotoxicity. Spred-2 knockout (KO) mice demonstrated exacerbated liver injury, an event that was associated with increased numbers of CD4(+) T, CD8(+) T and NK cells in the liver compared to the control. Levels of CXCL9/CXCL10 that attract and activate these cells were increased in Spred-2 KO-liver. Kupffer cells isolated from Spred-2 KO mice after APAP challenge expressed higher levels of CXCL9/CXCL10 than those from the control. Upon stimulation with APAP or IFN gamma, naive Kupffer cells from Spred-2 KO mice expressed higher levels of CXCL9/CXCL10. NK cell-depletion attenuated APAP-hepatotoxicity with lowered hepatic IFN gamma and decreased numbers of not only NK cells but also CD4(+) T and CD8(+) T cells in the liver. These results suggest that Spred-2 negatively regulates APAP-hepatotoxicity under the control of Kupffer cells and NK cells. (C) 2012 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.clim.2012.07.002

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  • ANCA-associated systemic vasculitis in Japan: clinical features and prognostic changes

    Kunihiro Yamagata, Joichi Usui, Chie Saito, Naoto Yamaguchi, Kouichi Hirayama, Kaori Mase, Masaki Kobayashi, Akio Koyama, Hitoshi Sugiyama, Kosaku Nitta, Takashi Wada, Eri Muso, Yoshihiro Arimura, Hirofumi Makino, Seiichi Matsuo

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   16 ( 4 )   580 - 588   2012年8月

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    記述言語:英語   出版者・発行元:SPRINGER  

    This study was conducted to standardize treatment and determine patient and renal outcome in Japanese anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis/rapidly progressive glomerulonephritis (AAV/RPGN) patients, because the prognosis of AAV/RPGN patients in Japan had been poor compared with that of other countries.
    The participants in this retrospective cohort study were 824 ANCA-positive RPGN patients, 705 of whom were only myeloperoxidase (MPO)-ANCA positive.
    Among the early-years cohort (group A; cases diagnosed between 1988 and 1998), patients frequently died due to opportunistic infection. Therefore, we recommended a reduced dose of prednisolone (oral prednisolone dose < 0.8 mg/kg/day) with or without cyclophosphamide for initial treatment of Japanese RPGN patients. After this recommendation, 1-year survival of the patients improved: 75% in group A, 79% in group B (between 1999 and 2002), and 81% in group C (after 2003). During the entire observation period, average serum creatinine level at the start of treatment decreased, and improvement of 1-year renal survival was also found (72% in group A, 83% in group B, and 83% in group C), while the recurrence rate was significantly increased in group C (0.05/patient-year in group A, 0.07/patient-year in group B, and 0.13/patient-year in group C).
    Oral prednisolone dose < 0.8 mg/kg/day with or without cyclophosphamide as an initial treatment could improve patient survival in older Japanese AAV/RPGN patients. However, maintenance treatment avoiding relapse should be established to improve renal outcomes.

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  • Acquired haemophilia in a patient with castleman's disease: a case report

    T. Katsuyama, K. E. Sada, A. Katayama, N. Hinamoto, H. Wakabayashi, T. Kawabata, H. Makino

    HAEMOPHILIA   18 ( 4 )   e360 - e362   2012年7月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    DOI: 10.1111/j.1365-2516.2012.02850.x

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  • EFFLUENT FREE RADICALS ARE ASSOCIATED WITH RESIDUAL RENAL FUNCTION AND PREDICT TECHNIQUE FAILURE IN PERITONEAL DIALYSIS PATIENTS

    Hiroshi Morinaga, Hitoshi Sugiyama, Tatsuyuki Inoue, Keiichi Takiue, Yoko Kikumoto, Masashi Kitagawa, Shigeru Akagi, Kazushi Nakao, Yohei Maeshima, Ikuko Miyazaki, Masato Asanuma, Makoto Hiramatsu, Hirofumi Makino

    PERITONEAL DIALYSIS INTERNATIONAL   32 ( 4 )   453 - 461   2012年7月

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    記述言語:英語   出版者・発行元:MULTIMED INC  

    Objective: Residual renal function (RRF) is associated with low oxidative stress in peritoneal dialysis (PD). In the present study, we investigated the relationship between the impact of oxidative stress on RRF and patient outcomes during PD.
    Methods: Levels of free radicals (FRs) in effluent from the overnight dwell in 45 outpatients were determined by electron spin resonance spectrometry. The FR levels, clinical parameters, and the level of 8-hydroxy-2'-deoxyguanosine were evaluated at study start. The effects of effluent FR level on technique and patient survival were analyzed in a prospective cohort followed for 24 months.
    Results: Levels of effluent FRs showed significant negative correlations with daily urine volume and residual renal Kt/V, and positive correlations with plasma beta(2)-microglobulin and effluent 8-hydroxy-2'-deoxyguanosine. A highly significant difference in technique survival (p < 0.05), but not patient survival, was observed for patients grouped by effluent FR quartile. The effluent FR level was independently associated with technique failure after adjusting for patient age, history of cardiovascular disease, and presence of diabetes mellitus (p < 0.001). The level of effluent FRs was associated with death-censored technique failure in both univariate (p < 0.001) and multivariate (p < 0.01) hazard models. Compared with patients remaining on PD, those withdrawn from the modality had significantly higher levels of effluent FRs (p < 0.005).
    Conclusions: Elevated effluent FRs are associated with RRF and technique failure in stable PD patients. These findings highlight the importance of oxidative stress as an unfavorable prognostic factor in PD and emphasize that steps should be taken to minimize oxidative stress in these patients. Perit Dial Int 2012; 32(4): 453-461

    DOI: 10.3747/pdi.2011.00032

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  • Serum Vaspin Concentrations Are Closely Related to Insulin Resistance, and rs77060950 at SERPINA12 Genetically Defines Distinct Group with Higher Serum Levels in Japanese Population

    Sanae Teshigawara, Jun Wada, Kazuyuki Hida, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Izumi Iseda, Yuichi Matsushita, Nobuyuki Miyatake, John F. McDonald, Kikuko Hotta, Hirofumi Makino

    JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM   97 ( 7 )   E1202 - E1207   2012年7月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    Context: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats.
    Objective: We investigated genetic and nongenetic factors that define serum concentrations of vaspin.
    Design, Setting and Participants: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138).
    Results: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 +/- 0.04 vs. 0.86 +/- 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 +/- 0.4 ng/ml), CA (18.4 +/- 9.6 ng/ml), and AA (30.5 +/- 5.1 ng/ml) (P < 2 x 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950.
    Conclusions: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950. (J Clin Endocrinol Metab 97: E1202-E1207, 2012)

    DOI: 10.1210/jc.2011-3297

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  • Regulatory role of kit ligand-c-kit interaction and oocyte factors in steroidogenesis by rat granulosa cells

    Tomoko Miyoshi, Fumio Otsuka, Eri Nakamura, Kenichi Inagaki, Kanako Ogura-Ochi, Naoko Tsukamoto, Masaya Takeda, Hirofumi Makino

    MOLECULAR AND CELLULAR ENDOCRINOLOGY   358 ( 1 )   18 - 26   2012年7月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Although kit ligand (KL)-c-kit interaction is known to be critical for oogenesis and folliculogenesis, its role in ovarian steroidogenesis has yet to be elucidated. We studied the impact of KL-c-kit interaction in regulation of steroidogenesis using rat oocyte/granulosa cell co-culture. In the presence of oocytes, soluble KL suppressed FSH-induced estradiol production and aromatase mRNA expression without affecting FSH-induced progesterone production. The KL effect on steroidogenesis was interrupted by an anti-c-kit neutralizing antibody, suggesting that KL-c-kit interaction is involved in suppression of estrogen by granulosa cells through oocyte c-kit action. The cAMP-PKA pathway activity was not directly involved in the estrogen regulation by KL-c-kit action. It was of note that KL treatment increased the expression levels of oocyte-derived FGF-8, GDF-9 and BMP-6, while it reduced the expression levels of oocyte-derived BMP-15 in the oocyte-granulosa cell co-culture. Given the findings that FGF-8, but not GDF-9, BMP-6 or -15, suppressed FSH-induced estrogen production by granulosa cells, oocyte-derived FGF-8 is linked to suppression of FSH-induced estrogen production through the KL-c-kit interaction. Furthermore, the suppression of FSH-induced estrogen production by KL in the co-culture was reversed by a FGF receptor kinase inhibitor and the effect of the inhibitor was enhanced in combination with extracellular-domain protein of BMPRII, which interferes with BMP-15 and GDF-9 activities. Thus, the actions of endogenous oocyte factors including FGF-8 and BMP-15/GDF-9 were involved in the KL activity that inhibited FSH-induced estradiol production. Collectively, the results indicate that KL-c-kit interaction plays a role in estrogenic regulation through oocyte-granulosa cell communication. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

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  • A case of focal segmental glomerulosclerosis in an adult patient with hypogammaglobulinemia superimposed on membranoproliferative glomerulonephritis in childhood

    Kenji Tsuji, Haruhito Adam Uchida, Tetsuichirou Ono, Tatsuyuki Inoue, Katsuji Shinagawa, Shinji Kitamura, Yohei Maeshima, Hitoshi Sugiyama, Hirofumi Makino

    BMC NEPHROLOGY   13   46 - 46   2012年6月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Common variable immunodeficiency (CVID) is a disorder characterized by hypogammaglobulinemia without a known predisposing cause.
    Case presentation: We report a 36-year-old man who had suffered membranoproliferative glomerulonephritis (MPGN) in his childhood, later diagnosed with CVID at 35 years of age. He presented at our hospital with signs of proteinuria. A renal biopsy revealed he suffered from focal segmental glomerulosclerosis (FSGS), possibly due to obesity and hypertension, not CVID - associated MPGN.
    Conclusion: This is the first case report of FSGS in a CVID patient. In this case, we have to pay attention not only to the treatment of obesity and hypertension for FSGS but also to the recurrence of immune-complex glomerulonephritis such as MPGN, in case of the restoration of hypogammaglobulinemia.

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  • Sustained-release prostacyclin analog ONO-1301 ameliorates tubulointerstitial alterations in a mouse obstructive nephropathy model

    Tatsuyo Nasu, Masaru Kinomura, Katsuyuki Tanabe, Hiroko Yamasaki, Su Le Htay, Daisuke Saito, Norikazu Hinamoto, Hiroyuki Watatani, Haruyo Ujike, Yoshinori Suzuki, Takeshi Sugaya, Hitoshi Sugiyama, Yoshiki Sakai, Kunio Matsumoto, Yohei Maeshima, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY   302 ( 12 )   F1616 - F1629   2012年6月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Nasu T, Kinomura M, Tanabe K, Yamasaki H, Htay SL, Saito D, Hinamoto N, Watatani H, Ujike H, Suzuki Y, Sugaya T, Sugiyama H, Sakai Y, Matsumoto K, Maeshima Y, Makino H. Sustained-release prostacyclin analog ONO-1301 ameliorates tubulointerstitial alterations in a mouse obstructive nephropathy model. Am J Physiol Renal Physiol 302: F1616-F1629, 2012. First published March 12, 2012; doi: 10.1152/ajprenal.00538.2011.-Tubulointersti-tial injuries are crucial histological alterations that predict the deterioration of renal function in chronic kidney disease. ONO-1301, a novel sustained-release prostacyclin analog, accompanied by thromboxane synthase activity, exerts therapeutic effects on experimental pulmonary hypertension, lung fibrosis, cardiomyopathy, and myocardial ischemia, partly associated with the induction of hepatocyte growth factor (HGF). In the present study, we examined the therapeutic efficacies of ONO-1301 on tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO). After inducing unilateral ureteral obstruction in C57/BL6J mice, a single injection of sustained-release ONO-1301 polymerized with poly (D,L-lactic-co-glycolic acid) sustained-release ONO-1301 (SR-ONO) significantly suppressed interstitial fibrosis, accumulation of types I and III collagen, increase in the number of interstitial fibroblast-specific protein-1 (FSP-1)(+) cells, and interstitial infiltration of monocytes/macrophages (F4/80(+)) in the obstructed kidneys (OBK; day 7). Treatment with SR-ONO significantly suppressed the increase of the renal levels of profibrotic factor TGF-beta and phosphorylation of Smad2/3, and elevated the renal levels of HGF in the OBK. In cultured mouse proximal tubular epithelial cells (mProx24), ONO-1301 significantly ameliorated the expression of fibroblast-specific protein-1 and alpha-smooth muscle actin as well as phosphorylation of Smad3 and increased the expression of zonula occludens-1 and E-cadherin in the presence of TGF-beta 1 as detected by immunoblot and immunocytochemistry, partly dependent on PGI(2) receptor-mediated signaling. Administration of rabbit anti-HGF antibodies, but not the control IgG, partly reversed the suppressive effects of SR-ONO on tubulointerstitial injuries in the OBK. Taken together, our findings suggest the potential therapeutic efficacies of ONO-1301 in suppressing tubulointerstitial alterations partly mediated via inducing HGF, an antifibrotic factor counteracting TGF-beta

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  • Severity-based treatment for Japanese patients with MPO-ANCA-associated vasculitis: the JMAAV study

    Shoichi Ozaki, Tatsuya Atsumi, Taichi Hayashi, Akihiro Ishizu, Shigeto Kobayashi, Shunichi Kumagai, Yasuyuki Kurihara, Manae S. Kurokawa, Hirofumi Makino, Hiroko Nagafuchi, Kimimasa Nakabayashi, Norihiro Nishimoto, Machi Suka, Yasuhiko Tomino, Hidehiro Yamada, Kunihiro Yamagata, Masaharu Yoshida, Wako Yumura

    MODERN RHEUMATOLOGY   22 ( 3 )   394 - 404   2012年6月

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    記述言語:英語   出版者・発行元:SPRINGER  

    We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.

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  • Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse

    Katsuyuki Tanabe, Miguel A. Lanaspa, Wataru Kitagawa, Christopher J. Rivard, Makoto Miyazaki, Jelena Klawitter, George F. Schreiner, Moin A. Saleem, Peter W. Mathieson, Hirofumi Makino, Richard J. Johnson, Takahiko Nakagawa

    AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY   302 ( 9 )   F1151 - F1160   2012年5月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Tanabe K, Lanaspa MA, Kitagawa W, Rivard CJ, Miyazaki M, Klawitter J, Schreiner GF, Saleem MA, Mathieson PW, Makino H, Johnson RJ, Nakagawa T. Nicorandil as a novel therapy for advanced diabetic nephropathy in the eNOS-deficient mouse. Am J Physiol Renal Physiol 302: F1151-F1160, 2012. First published February 15, 2012; doi:10.1152/ajprenal.00596.2011.-Nicorandil is an orally available drug that can act as a nitric oxide donor, an antioxidant, and an ATP-dependent K channel activator. We hypothesized that it may have a beneficial role in treating diabetic nephropathy. We administered nicorandil to a model of advanced diabetic nephropathy (the streptozotocin-induced diabetes in mice lacking endothelial nitric oxide synthase, eNOSKO); controls included diabetic eNOS KO mice without nicorandil and nondiabetic eNOS KO mice treated with either nicorandil or vehicle. Mice were treated for 8 wk. Histology, blood pressure, and renal function were determined. Additional studies involved examining the effects of nicorandil on cultured human podocytes. Here, we found that nicorandil did not affect blood glucose levels, blood pressure, or systemic endothelial function, but significantly reduced proteinuria and glomerular injury (mesangiolysis and glomerulosclerosis). Nicorandil protected against podocyte loss and podocyte oxidative stress. Studies in cultured podocytes showed that nicorandil likely protects against glucose-mediated oxidant stress via the ATP-dependent K channel as opposed to its NO-stimulating effects. In conclusion, nicorandil may be beneficial in diabetic nephropathy by preserving podocyte function. We recommend clinical trials to determine whether nicorandil may benefit diabetic nephropathy or other conditions associated with podocyte dysfunction.

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  • Cholecystokinin Plays a Novel Protective Role in Diabetic Kidney Through Anti-inflammatory Actions on Macrophage Anti-inflammatory Effect of Cholecystokinin

    Satoshi Miyamoto, Kenichi Shikata, Kyoko Miyasaka, Shinichi Okada, Motofumi Sasaki, Ryo Kodera, Daisho Hirota, Nobuo Kajitani, Tetsuharu Takatsuka, Hitomi Usui Kataoka, Shingo Nishishita, Chikage Sato, Akihiro Funakoshi, Hisakazu Nishimori, Haruhito Adam Uchida, Daisuke Ogawa, Hirofumi Makino

    DIABETES   61 ( 4 )   897 - 907   2012年4月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    Inflammatory process is involved in the pathogenesis of diabetic nephropathy. In this article, we show that cholecystokinin (CCK) is expressed in the kidney and exerts renoprotective effects through its anti-inflammatory actions. DNA microarray showed that CCK was upregulated in the kidney of diabetic wild-type (WT) mice but not in diabetic intracellular adhesion molecule-1 knockout mice. We induced diabetes in CCK-1 receptor (CCK-1R) and CCK-2R double-knockout (CCK-1R(-/-),-2R(-/-)) mice, and furthermore, we performed a bone marrow transplantation study using CCK-1R(-/-) mice to determine the role of CCK-1R on macrophages in the diabetic kidney. Diabetic CCK-1R(-/-),-2R(-/-) mice revealed enhanced albuminuria and inflammation in the kidney compared with diabetic WT mice. In addition, diabetic WT mice with CCK-1R(-/-) bone marrow-derived cells developed more albuminuria than diabetic CCK-1R(-/-) mice with WT bone marrow-derived cells. Administration of sulfated cholecystokinin octapeptide (CCK-8S) ameliorated albuminuria, podocyte loss, expression of proinflammatory genes, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, CCK-8S inhibited both expression of tumor necrosis factor-alpha and chemotaxis in cultured THP-1 cells. These results suggest that CCK suppresses the activation of macrophage and expression of proinflammatory genes in diabetic kidney. Our findings may provide a novel strategy of therapy for the early stage of diabetic nephropathy. Diabetes 61:897-907, 2012

    DOI: 10.2337/db11-0402

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  • RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21(Cip1) pathway in adipocytes

    Atsuko Nakatsuka, Jun Wada, Kazuyuki Hida, Aya Hida, Jun Eguchi, Sanae Teshigawara, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Daisuke Ogawa, Hiroyuki Kagechika, Hirofumi Makino

    JOURNAL OF PATHOLOGY   226 ( 5 )   784 - 795   2012年4月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    The peroxisome proliferator activated receptor-gamma (PPAR gamma) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G(0)/G(1) cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G(0) + G(1) ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G(0)/G(1) cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G(0)/G(1) cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    DOI: 10.1002/path.3001

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  • Suppression of Adiponectin by Aberrantly Glycosylated IgA1 in Glomerular Mesangial Cells In Vitro and In Vivo

    Tatsuyuki Inoue, Hitoshi Sugiyama, Masashi Kitagawa, Keiichi Takiue, Hiroshi Morinaga, Ayu Ogawa, Yoko Kikumoto, Shinji Kitamura, Yohei Maeshima, Hirofumi Makino

    PLOS ONE   7 ( 3 )   33965 - 33965   2012年3月

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    記述言語:英語   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    The pathogenesis of IgA nephropathy (IgAN) may be associated with the mesangial deposition of aberrantly glycosylated IgA1. To identify mediators affected by aberrantly glycosylated IgA1 in cultured human mesangial cells (HMCs), we generated enzymatically modified desialylated and degalactosylated (deSial/deGal) IgA1. The state of deglycosylated IgA1 was confirmed by lectin binding to Helix aspersa (HAA) and Sambucus nigra (SNA). In the cytokine array analysis, 52 proteins were upregulated and 34 were downregulated in HMCs after stimulation with deSial/deGal IgA1. Among them, the secretion of adiponectin was suppressed in HMCs after stimulation with deSial/deGal IgA1. HMCs expressed mRNAs for adiponectin and its type 1 receptor, but not the type 2 receptor. Moreover, we revealed a downregulation of adiponectin expression in the glomeruli of renal biopsy specimens from patients with IgAN compared to those with lupus nephritis. We also demonstrated that aberrantly glycosylated IgA1 was deposited in the mesangium of patients with IgAN by dual staining of HAA and IgA. Moreover, the urinary HAA/SNA ratio of lectin binding was significantly higher in IgAN compared to other kidney diseases. Since adiponectin has anti-inflammatory effects, including the inhibition of adhesion molecules and cytokines, these data suggest that the local suppression of this adipokine by aberrantly glycosylated IgA1 could be involved in the regulation of glomerular inflammation and sclerosis in IgAN.

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  • Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

    Jiro Suzuki, Fumio Otsuka, Yoshinori Matsumoto, Kenichi Inagaki, Tomoko Miyoshi, Masaya Takeda, Naoko Tsukamoto, Eri Nakamura, Kanako Ogura, Hirofumi Makino

    HYPERTENSION RESEARCH   35 ( 3 )   312 - 317   2012年3月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Recent studies have shown that bone morphogenetic proteins (BMPs), particularly BMP-7, have an inhibitory role in the development of various renal diseases. We previously reported antagonistic effects of BMPs on renal mesangial cell proliferation induced by aldosterone (Aldo) in vitro. In the present study, we investigated in vivo roles of BMPs in Aldo-induced renal glomerular injury. BALB/c mice aged 6 weeks were treated with Aldo injection (5 mu g per day, intraperitoneally) and/or oral administration of high-salt (2%) water for 9 weeks. Systemic blood pressure, body weight, kidney weight and daily proteinuria were not significantly changed by Aldo and/or high-salt treatment. However, renal histological examination revealed increases in glomerular cellularity and glomerular diameter in the groups treated with Aldo injection and high-salt administration. Immunohistochemistry demonstrated expression of BMP-4 and -7 in the glomerular mesangial region. Aldo causes renal glomerular damage by stimulating mesangial cell proliferation and increasing extracellular matrix via the mineralocorticoid receptor (MR). MR messenger RNA (mRNA) expression in the renal cortex was transiently increased by 3-week treatment with Aldo and high-salt intake, but was decreased by 9-week treatment. Furthermore, the expression levels of BMP-4 and -7 mRNA were enhanced in the renal cortex treated with Aldo and high-salt administration. These findings suggest that the renal BMP system is activated by Aldo under the condition of high-salt exposure, which may have a key role in antagonizing glomerular damage in vivo. Hypertension Research (2012) 35, 312-317; doi:10.1038/hr.2011.186; published online 10 November 2011

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  • Risk Factors Associated with Relapse in Japanese Patients with Microscopic Polyangiitis

    Takashi Wada, Akinori Hara, Yoshihiro Arimura, Ken-El Sada, Hirofumi Makino

    JOURNAL OF RHEUMATOLOGY   39 ( 3 )   545 - 551   2012年3月

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    記述言語:英語   出版者・発行元:J RHEUMATOL PUBL CO  

    Objective. We retrospectively studied the risk factors associated with relapse during remission maintenance therapy for myeloperoxidase-antineutrophil cytoplasmic autoantibody (MPO-ANCA)-positive microscopic polyangiitis (MPA).
    Methods. Sixty-two patients diagnosed with MPA according to the European Medicines Agency classification algorithm during a 2-year period from January 1, 2005, to December 31, 2006, and who achieved remission after the first remission-induction therapy, were examined (registration no. UMIN000001785).
    Results. The patient group comprised 25 men and 37 women aged 70.0 +/- 8.9 years. The mean observation period was 30.2 +/- 15.9 months. The rate of relapse was 24.2% (15/62), and mean interval between remission and relapse was 16.9 +/- 13.5 months. During maintenance therapy following remission, the risk of relapse increased when the reduction rate of prednisolone increased above 0.8 mg/month (OR 12.6, 95% CI 2.2-97.9). Proteinuria at the start of maintenance therapy (regression coefficient 1.991 +/- 0.758, p < 0.05) and the change in red blood cell counts in urine during the period from the start of maintenance therapy to the final observation (regression coefficient 0.126 +/- 0.040, p < 0.01) were identified as risk factors influencing the vasculitis damage index.
    Conclusion. In Japan, relapse of MPO-ANCA-positive MPA may be associated with the reduction rate of oral prednisolone administration during maintenance therapy. (First Release Dec 15 2011; J Rheumatol 2012;39:545-51; doi:10.3899/jrheum.110705)

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  • Acatalasemic mice are mildly susceptible to adriamycin nephropathy and exhibit increased albuminuria and glomerulosclerosis

    Keiichi Takiue, Hitoshi Sugiyama, Tatsuyuki Inoue, Hiroshi Morinaga, Yoko Kikumoto, Masashi Kitagawa, Shinji Kitamura, Yohei Maeshima, Da-Hong Wang, Noriyoshi Masuoka, Keiki Ogino, Hirofumi Makino

    BMC NEPHROLOGY   13   14 - 14   2012年3月

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Background: Catalase is an important antioxidant enzyme that regulates the level of intracellular hydrogen peroxide and hydroxyl radicals. The effects of catalase deficiency on albuminuria and progressive glomerulosclerosis have not yet been fully elucidated. The adriamycin (ADR) nephropathy model is considered to be an experimental model of focal segmental glomerulosclerosis. A functional catalase deficiency was hypothesized to exacerbate albuminuria and the progression of glomerulosclerosis in this model.
    Methods: ADR was intravenously administered to both homozygous acatalasemic mutant mice (C3H/AnLCs(b)Cs(b)) and control wild-type mice (C3H/AnLCs(a)Cs(a)). The functional and morphological alterations of the kidneys, including albuminuria, renal function, podocytic, glomerular and tubulointerstitial injuries, and the activities of catalase were then compared between the two groups up to 8 weeks after disease induction. Moreover, the presence of a mutation of the toll-like receptor 4 (tlr4) gene, which was previously reported in the C3H/HeJ strain, was investigated in both groups.
    Results: The ADR-treated mice developed significant albuminuria and glomerulosclerosis, and the degree of these conditions in the ADR-treated acatalasemic mice was higher than that in the wild-type mice. ADR induced progressive renal fibrosis, renal atrophy and lipid peroxide accumulation only in the acatalasemic mice. In addition, the level of catalase activity was significantly lower in the kidneys of the acatalasemic mice than in the wild-type mice during the experimental period. The catalase activity increased after ADR injection in wild-type mice, but the acatalasemic mice did not have the ability to increase their catalase activity under oxidative stress. The C3H/AnL strain was found to be negative for the tlr4 gene mutation.
    Conclusions: These data indicate that catalase deficiency plays an important role in the progression of renal injury in the ADR nephropathy model.

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  • Bone morphogenetic protein-3b (BMP-3b) inhibits osteoblast differentiation via Smad2/3 pathway by counteracting Smad1/5/8 signaling

    Yoshinori Matsumoto, Fumio Otsuka, Jun Hino, Tomoko Miyoshi, Mariko Takano, Mikiya Miyazato, Hirofumi Makino, Kenji Kangawa

    MOLECULAR AND CELLULAR ENDOCRINOLOGY   350 ( 1 )   78 - 86   2012年3月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Despite the involvement of BMP-3b (also called GDF-10) in osteogenesis, embryogenesis and adipogenesis, the functional receptors and intracellular signaling of BMP-3b have yet to be elucidated. In the present study, we investigated the cellular mechanism of BMP-3b in osteoblast differentiation using mouse myoblastic C2C12 cells. BMP-3b stimulated activin/TGF-beta-responsive promoter activities. The stimulatory actions of BMP-3b on activin/TGF-beta-responsive activities were suppressed by co-treatment with BMP-2. BMP-responsive promoter activities stimulated by BMP-2 were significantly inhibited by treatment with BMP-3b. BMP-3b suppressed the expression of osteoblastic markers including Runx2, osteocalcin and type-1 collagen induced by BMP-2, -4, -6 and -7. BMP-2-induced Smad1/5/8 phosphorylation and mRNA levels of the BMP target gene Id-1 were suppressed by co-treatment with BMP-3b, although BMP-3b failed to activate Smad1/5/8 signaling. Of interest, the BMP-3b suppression of BMP-2-induced Id-1 expression was not observed in cells overexpressing Smad4 molecules. On the other hand, BMP-3b directly activated Smad2/3 phosphorylation and activin/TGF-beta target gene PAI-1 mRNA expression, while BMP-2 suppressed BMP-3b-induced Smad2/3 signal activation. BMP-2 inhibition of BMP-3b-induced PAI-1 expression was also reversed by overexpression of Smad4. Analysis using inhibitors for BMP-Smad1/5/8 pathways revealed that these BMP-3b effects were mediated via receptors other than ALK-2, -3 and -6. Furthermore, results of inhibitory studies using extracellular domains for BMP receptor constructs showed that the activity of BMP-3b was functionally facilitated by a combination of ALK-4 and ActRIIA. Collectively, BMP-3b plays an inhibitory role in the process of osteoblast differentiation, in which BMP-3b and BMP-2 are mutually antagonistic possibly by competing with the availability of Smad4. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.mce.2011.11.023

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  • BMP action in the pituitary: Its possible role in modulating somatostatin sensitivity in pituitary tumor cells

    Fumio Otsuka, Naoko Tsukamoto, Tomoko Miyoshi, Yasumasa Iwasaki, Hirofumi Makino

    MOLECULAR AND CELLULAR ENDOCRINOLOGY   349 ( 2 )   105 - 110   2012年2月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    The existence of a functional bone morphogenetic protein (BMP) system in the pituitary has been recognized. Recent studies have provided evidence that BMPs elicit differential actions in the regulation of prolactin (PRL) and adrenocorticotropin (ACTH) release in lactotropinoma and corticotropinoma cells, respectively. BMPs play a key role in the modulation of somatostatin receptor (SSTR) sensitivity of lactosomatotrope cells in an autocrine/paracrine manner. In addition, SSTR action enhances BMP responsiveness in corticotrope cells. The functional link between BMP receptor signaling and SSTR actions may be crucial for individual tolerance to somatostatin analogs for controlling PRL and ACTH production. Adjustment of the endogenous SSTR sensitivity may be an effective strategy to inhibit the growth activity and hormonal productivity of intractable pituitary tumors. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.mce.2011.10.017

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  • Galectin-9 and T Cell Immunoglobulin Mucin-3 Pathway Is a Therapeutic Target for Type 1 Diabetes

    Motoko Kanzaki, Jun Wada, Koichi Sugiyama, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Jun Eguchi, Hisaya Akiba, Hideo Yagita, Hirofumi Makino

    ENDOCRINOLOGY   153 ( 2 )   612 - 620   2012年2月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-alpha, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-gamma in MIN6 cells, and Gal-9 was also expressed in the pancreatic beta-cells in NOD mice, suggesting Gal-9 may be released from pancreatic beta-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 mu M, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-alpha production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-alpha production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-alpha production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes. (Endocrinology 153: 612-620, 2012)

    DOI: 10.1210/en.2011-1579

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  • Interaction between gonadotropin-releasing hormone and bone morphogenetic protein-6 and -7 signaling in LβT2 gonadotrope cells.

    Takeda M, Otsuka F, Takahashi H, Inagaki K, Miyoshi T, Tsukamoto N, Makino H, Lawson MA

    Mol Cell Endocrinol   348 ( 1 )   147 - 154   2012年1月

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  • RAAS阻害薬.

    内田治仁, 槇野博史

    臨床に直結する腎疾患治療のエビデンス   136 - 140   2012年

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  • エリアMPOs-ANCA・PR3s-ANCA測定試薬による抗好中球細胞質抗体の基礎的・臨床的検討.

    糸島浩一, 鳥越佳子, 月田由香, 冨谷啓子, 岡田 健, 佐田憲映, 槇野博史

    医学と薬学   67 ( 3 )   477 - 484   2012年

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  • 重度の吸収障害でLT4投与法に苦慮した甲状腺機能低下症の一例.

    越智可奈子, 大塚文男, 中村絵里, 塚本尚子, 武田昌也, 稲垣兼一, 三好智子, 三村由香里, 小倉俊郎, 名和秀起, 槇野博史

    日本甲状腺学会雑誌 特集1ホルモン作用:作用機序と破綻による疾患   3 ( 1 )   41 - 45   2012年

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  • Inhibition of TNF-induced IL-6 by the TWEAK-Fn14 interaction in rheumatoid arthritis fibroblast like synoviocytes

    Jiro Yamana, Eric F. Morand, Tsuno Manabu, Katsue Sunahori, Kouji Takasugi, Hirofumi Makino, Masahiro Yamamura

    CELLULAR IMMUNOLOGY   272 ( 2 )   293 - 298   2012年

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Objectives: TNF-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily, has been shown to increase cytokine production by rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). In this study, we determined the effect of interaction between TWEAK and its receptor fibroblast growth factor-inducible-14 (Fn14) on cytokine expression in RAFLS.
    Methods: RAFLS were obtained from surgical synovial specimens and used at passage 5-10. Cytokine protein and mRNA expression were measured with ELISA and real time-PCR, respectively. Apoptotic cells were detected by TUNEL assay. RelB activation was detected by Western blot analysis.
    Results: TWEAK inhibited IL-6 production from total synovial cells from RA. TWEAK weakly induced FLS IL-6 and IL-8, but in contrast TWEAK dose-dependently inhibited IL-6 and IL-8 production by TNF alpha-activated FLS. TWEAK did not induce apoptosis in FLS but inhibited proliferation of TNF alpha-activated FLS. TWEAK induced RelB activation and suppressed IL-6 mRNA expression in TNF alpha-activated FLS and both of these phenomenon were abolished by inhibition of new protein synthesis with cycloheximide.
    Conclusions: TWEAK has a previously unsuspected inhibitory effect on cytokine production by TNF alpha-activated RAFLS. This observation suggests that the effects of TWEAK on cytokine expression varies with the pro-inflammatory context, and that in TNFa-activated states such as RA TWEAK may have a net inhibitory effect. (C) 2011 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.cellimm.2011.09.004

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  • The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome: a randomized controlled trial.

    Kanzaki M, Wada J, Kikumoto Y, Akagi S, Nakao K, Sugiyama H, Makino H

    Int J Nephrol Renovasc Dis   5   91 - 96   2012年

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  • オクトレオチドが著効した急性発症・原発不明の異所性ACTH症候群の1例.

    稲垣兼一, 大塚文男, 当真貴志雄, 越智可奈子, 中村絵里, 塚本尚子, 武田昌也, 三好智子, 三村由香里, 小倉俊郎, 槇野博史

    ACTH RELATED PEPTIDES   23   58 - 60   2012年

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  • A Case of Type 2 Diabetes and Metastatic Liver Cancer Exhibiting Hypercholesterolemia with Abnormal Lipoproteins

    Motoko Kanzaki, Jun Wada, Atsuko Nakatsuka, Sanae Teshigawara, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Junichiro Nasu, Kazuhide Yamamoto, Hirofumi Makino

    INTERNAL MEDICINE   51 ( 6 )   619 - 623   2012年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Although the appearance of abnormal lipoproteins in liver diseases is well known, the precise analyses of abnormal lipoproteins remain elusive. Here, we report a 71-year-old woman with type 2 diabetes whose serum cholesterol levels were elevated to 560 mg/dL over a 4-month period. High-performance liquid chromatography demonstrated the presence of lipoprotein-X and lipoprotein-Y and sigmoid colon cancer and multiple liver metastases were found by colonoscopy and computed tomography. Remission of the primary colon cancer and liver lesions was achieved by chemotherapy with oxaliplatin and fluorouracil and her serum cholesterol went back to basal levels associated with the disappearance of abnormal lipoproteins.

    DOI: 10.2169/internalmedicine.51.6486

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  • 序文.

    槇野博史

    腎臓症候群(第2版)上‐その他の腎臓疾患を含めて‐   17   1 - 1   2012年

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  • 頭痛・眼瞼下垂を契機に発見され下垂体卒中により 急速なGH低下を認めたアクロメガリーの1例.

    武田昌也, 大塚文男, 小倉可奈子, 中村絵里, 塚本尚子, 三好智子, 稲垣兼一, 槇野博史

    第7回アクロメガリーフォーラム記録集   32 - 32   2012年

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  • 心腎症候群(CRS).

    北川正史, 杉山 斉, 槇野博史

    腎臓症候群(第2版)上   17   15 - 26   2012年

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  • Ⅲ尿細管間質性腎症 特発性尿細管間質性腎炎(急性、慢性).

    菊本陽子, 杉山 斉, 槇野博史

    腎臓症候群(第2版)上‐その他の腎臓疾患を含めて‐   17   198 - 203   2012年

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  • 特集:糖尿病性腎症治療と腎症治療薬の新しい展望 第6章「腎症治療薬の新しい展望 3炎症をターゲットとした治療薬」.

    小寺 亮, 四方賢一, 槇野博史

    MEDICINAL   2 ( 2 )   86 - 94   2012年

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  • PPARアゴニスト.

    小川大輔, 槇野博史

    MEDICINAL   2   102 - 107   2012年

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  • 各種病態にみられる腎障害 膠原病、血管炎 多発血管炎性肉芽腫症(Wegener肉芽腫症).

    佐田憲映, 槇野博史

    腎臓症候群(第2版)下‐その他の腎臓疾患を含めて‐   18   504 - 508   2012年

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  • 肥満関連腎症.

    和田 淳, 槇野博史

    腎臓症候群第2版(下)   18   376 - 382   2012年

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  • Ⅻ 各種病態にみられる腎障害 その他の病態 アミロイドーシス.

    瀧上慶一, 杉山 斉, 槇野博史

    新領域別症候群シリーズ   18   733 - 738   2012年

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  • 慢性腎臓病管理と病診連携.

    木野村 賢, 前島洋平, 槇野博史

    Modern Physician   32 ( 4 )   504 - 504   2012年

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  • 高カルシウム血症性腎症.

    山崎浩子, 前島洋平, 槇野博史

    腎臓症候群 第2版(下)   18   334 - 337   2012年

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  • 慢性腎臓病この10年と今後の展望.

    槇野博史

    日本内科学会雑誌   101 ( 5 )   1233 - 1235   2012年

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  • 核内受容体制御による糖尿病性腎症治療の可能性.

    小川大輔, 槇野博史

    糖尿病合併症   26   156 - 160   2012年

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  • 座談会 糖尿病、慢性腎臓病(CKD)から身を守るために.

    槇野博史, 門脇 孝, 宮本髙宏

    別冊がんサポート ストップ糖尿病・腎臓病   8 - 14   2012年

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  • インクレチンの臓器保護作用 ~インクレチンの腎保護作用~.

    小寺 亮, 槇野博史

    医学のあゆみ   241 ( 7 )   533 - 538   2012年

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  • 1.腎臓病の発見(症状・検査異常など).

    菊本陽子, 杉山 斉, 槇野博史

    腎疾患治療マニュアル2012-13   72   9 - 14   2012年

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  • 核内受容体アゴニスト.

    小川大輔, 槇野博史

    月刊糖尿病   7   118 - 123   2012年

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  • 糖尿病性腎症.

    斎藤大輔, 前島洋平, 槇野博史

    腎臓リハビリテーション   130 - 133   2012年

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  • Ⅸ.糖尿病合併症・糖尿病関連疾患 各種糖尿病合併症の概念・成因・診断・治療 糖尿病性細小血管症 糖尿病性腎症 糖尿病性腎症の成因.

    小川大輔, 槇野博史

    最新臨床糖尿病学(下)‐糖尿病学の最新動向‐   70 ( 5 )   389 - 392   2012年

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  • IX. 糖尿病合併症・糖尿病関連疾患 糖尿病性腎症の成因.

    小川大輔, 槇野博史

    日本臨床増刊 最新臨床糖尿病学 下   389 - 392   2012年

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  • 4.糖尿病性腎症の病態に立脚した治療.

    槇野博史

    日本内科学会雑誌   101 ( 9 )   2488 - 2496   2012年

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  • 多施設PD合同レジストリー ‐前向きコホート研究によるエビデンス創出を目指して‐.

    杉山 斉, 伊藤恭彦, 鶴屋和彦, 吉田寿子, 丸山弘樹, 後藤 眞, 中山昌明, 森永裕士, 槇野博史, 松尾清一

    腎と透析   73   22 - 24   2012年

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  • Development of Angiotensin II-induced Abdominal Aortic Aneurysms Is Independent of Catalase in Mice

    Haruhito A. Uchida, Hitoshi Sugiyama, Keiichi Takiue, Yoko Kikumoto, Tatsuyuki Inoue, Hirofumi Makino

    JOURNAL OF CARDIOVASCULAR PHARMACOLOGY   58 ( 6 )   633 - 638   2011年12月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Chronic infusion of angiotensin II (AngII) into mice augments the development of abdominal aortic aneurysms (AAAs). Catalase is an important antioxidant enzyme in cellular peroxisome, and it physiologically maintains tissue and cellular redox homeostasis and thus plays a central role in defense against oxidative stress. The purpose of this study was to define whether deficiency of catalase influences AngII-induced AAAs. Male acatalasemic (C3H/AnLCs(b)Cs(b)) mice and wild-type (C3H/AnLCsaCsa) mice (8-12 weeks old, N = 24 and 25, respectively) were fed a normal chow for 5 weeks. After 1 week of acclimtion, mice were infused subcutaneously with AngII (1000 ng.kg(-1).min(-1)) by osmotic minipumps for 4 weeks. AngII increased systolic blood pressure equivalently in both groups. Acatalasemia had no effect on serum cholesterol concentrations. The body weight of acatalasemic mice was slightly greater than that of wild-type mice (P = 0.008). Although aortic catalase activity in acatalasemic mice was significantly low (P < 0.001), acatalasemia had no significant effect on the incidence of AngII-induced AAA formation (acatalasemia, 23%; wild, 21%), ex vivo measurement of maximal diameter of abdominal aorta (acatalasemia, 1.22 +/- 0.29 mm; wild, 1.21 +/- 0.17 mm), or aortic deposition of lipid peroxidation products such as 4-hydroxy-2-nonenal. The development of AngII-induced AAAs is independent of catalase.

    DOI: 10.1097/FJC.0b013e3182317196

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  • Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study

    E. Imai, J. C. N. Chan, S. Ito, T. Yamasaki, F. Kobayashi, M. Haneda, H. Makino

    DIABETOLOGIA   54 ( 12 )   2978 - 2986   2011年12月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Aims/hypothesis The renal and cardiovascular protective effects of angiotensin receptor blocker (ARB) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor (ACEI).
    Methods We examined the effects of olmesartan, an ARB, on primary composite outcome of doubling of serum creatinine, endstage renal disease and death in type 2 diabetic patients with overt nephropathy. Secondary outcome included composite cardiovascular outcomes, changes in renal function and proteinuria. Randomisation and allocation to trial group were carried out by a central computer system. Participants, caregivers, the people carrying out examinations and people assessing the outcomes were blinded to group assignment.
    Results Five hundred and seventy-seven (377 Japanese, 200 Chinese) patients treated with antihypertensive therapy (73.5% [n=424] received concomitant ACEI), were given either once-daily olmesartan (10-40 mg) (n=288) or placebo (n=289) over 3.2 +/- 0.6 years (mean +/- SD). In the olmesartan group, 116 developed the primary outcome (41.1%) compared with 129 (45.4%) in the placebo group (HR 0.97, 95% CI 0.75, 1.24; p=0.791). Olmesartan significantly decreased blood pressure, proteinuria and rate of change of reciprocal serum creatinine. Cardiovascular death was higher in the olmesartan group than the placebo group (ten vs three cases), whereas major adverse cardiovascular events (cardiovascular death plus non-fatal stroke and myocardial infarction) and all-cause death were similar between the two groups (major adverse cardiovascular events 18 vs 21 cases, all-cause deaths; 19 vs 20 cases). Hyperkalaemia was more frequent in the olmesartan group than the placebo group (9.2% vs 5.3%).
    Conclusions/interpretation Olmesartan was well tolerated but did not improve renal outcome on top of ACEI.

    DOI: 10.1007/s00125-011-2325-z

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  • Decreasing Abdominal Circumference Is Associated with Improving Estimated Glomerular Filtration Rate (eGFR) with Lifestyle Modification in Japanese Men: A Pilot Study

    Nobuyuki Miyatake, Kenichi Shikata, Hirofumi Makino, Takeyuki Numata

    ACTA MEDICA OKAYAMA   65 ( 6 )   363 - 367   2011年12月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The link between changes in a subject's metabolic syndrome components and his estimated glomerular filtration rate (eGFR) was evaluated in healthy Japanese men. We used data from 120 Japanese men (45.5 +/- 8.4 years) with a 1-year follow up. eGFR was defined by a new equation developed for Japan. There were no significant differences in eGFR between men with and without metabolic syndrome components at baseline. Subjects were given advice for dietary and lifestyle improvement. At the 1-year follow up, almost all metabolic syndrome components were significantly improved. However, eGFR was significantly decreased. The changes in eGFR were weakly correlated with abdominal circumference (r = -0.232, p = 0.0106). A decrease in abdominal circumference may be associated with improving eGFR in Japanese men.

    DOI: 10.18926/AMO/47261

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  • Two novel mutations of lecithin:cholesterol acyltransferase (LCAT) gene and the influence of APOE genotypes on clinical manifestations

    Akihiro Katayama, Jun Wada, Hitomi Usui Kataoka, Hiroko Yamasaki, Sanae Teshigawara, Takahiro Terami, Kentaro Inoue, Motoko Kanzaki, Kazutoshi Murakami, Atsuko Nakatsuka, Hitoshi Sugiyama, Norio Koide, Hideaki Bujo, Hirofumi Makino

    NDT Plus   4 ( 5 )   299 - 302   2011年10月

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    記述言語:英語  

    Familial lecithin:cholesterol acyltransferase deficiency (FLD) is an autosomal recessive disorder characterized by corneal opacity, hemolytic anemia, low high-density lipoprotein cholesterol (HDL-C) and proteinuria. Two novel lecithin:cholesterol acyltransferase (LCAT) mutations[c.278 C&gt
    T (p.Pro69Leu)
    c.950 T&gt
    C (p.Met293Thr)] were identified in a 27-year-old man and in a 30-year-old woman, respectively. Both patients manifested corneal opacity, hemolytic anemia, low low-density lipoprotein cholesterol and HDL-C and proteinuria. Lipid deposits with vacuolar lucent appearance in glomerular basement membranes were observed in both cases. APOE genotype was also investigated: the first case results ε4/ε3, the second ε2/ε2
    however, they shared a similar phenotype characterized by the presence of intermediate-density lipoproteins (IDL) remnant and the absence of lipoprotein-X. In conclusion, our findings suggest that APOE ε2/ε2 may not be the major determinant gene for the appearance of IDL in FLD patients. © 2011 The Author.

    DOI: 10.1093/ndtplus/sfr091

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  • Proposal for diagnostic criteria for IgG4-related kidney disease

    Mitsuhiro Kawano, Takako Saeki, Hitoshi Nakashima, Shinichi Nishi, Yutaka Yamaguchi, Satoshi Hisano, Nobuaki Yamanaka, Dai Inoue, Motohisa Yamamoto, Hiroki Takahashi, Hideki Nomura, Takashi Taguchi, Hisanori Umehara, Hirofumi Makino, Takao Saito

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   15 ( 5 )   615 - 626   2011年10月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Background IgG4-related disease has attracted wide attention recently. It is characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive plasma cells into multiple organs, with the kidney being one representative target. Although several sets of diagnostic criteria for autoimmune pancreatitis (AIP) are available and renal lesion is recognized as an extra-pancreatic manifestation of AIP, it is difficult to differentiate IgG4-related tubulointerstitial nephritis (TIN) without AIP from other types of TIN. To clarify the entity of IgG4-related kidney disease (IgG4-RKD) and support in-depth studies, the Japanese Society of Nephrology has established a working group to prepare diagnostic criteria for IgG4-RKD.
    Method The working group analyzed 41 patients with IgG4-RKD, and collected the following data to devise a diagnostic algorithm and diagnostic criteria for IgG4-RKD: clinical features including extra-renal organ involvement, urinalysis and serological features including serum IgG4 levels, imaging findings demonstrated by computed tomography (CT), renal histology with IgG4 immuno-staining, and response to steroid therapy.
    Results The conditions for criteria are as follows. (1) Presence of some kidney damage, as manifested by abnormal urinalysis or urine marker(s) and/or decreased kidney function with either elevated serum IgG level, hypocomplementemia, or elevated serum IgE level. (2) Kidney imaging studies showing abnormal renal imaging findings, i.e., multiple low density lesions on enhanced CT, diffuse kidney enlargement, hypovascular solitary mass in the kidney, and hypertrophic lesion of the renal pelvic wall without irregularity of the renal pelvic surface. (3) Serum IgG4 level exceeding 135 mg/dl. (4) Renal histology showing two abnormal findings: (a) dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/high power field (HPF) and/or ratio of IgG4-positive plasma cells/IgG positive plasma cells >40%. (b) Characteristic 'storiform' fibrosis surrounding nests of lymphocytes and/or plasma cells. (5) Extra-renal histology showing dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/HPF and/or ratio of IgG4-positive plasma cells/IgG-positive plasma cells >40%. The diagnosis is classified into 3 stages of definite, probable and possible according to the combinations of the above conditions. Thirty-nine cases (95.1%) were diagnosed with IgG4-RKD according to the criteria.
    Conclusion The provisional criteria and algorithm appear to be useful for clarifying the entity of IgG4-RKD and seeking underlying IgG4-RKD cases; however, further experience is needed to confirm the validity of these criteria.

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  • Risk Factors for Infection in Patients with Remitted Rheumatic Diseases Treated with Glucocorticoids

    Yoshinori Matsumoto, Ken-ei Sada, Mariko Takano, Noriko Toyota, Ryutaro Yamanaka, Koichi Sugiyama, Hiroshi Wakabayashi, Tomoko Kawabata, Fumio Otsuka, Hirofumi Makino

    ACTA MEDICA OKAYAMA   65 ( 5 )   329 - 334   2011年10月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    It is well known that infection is one of the major causes of morbidity and mortality in rheumatic disease patients treated with high-dose glucocorticoids, especially in the early phase after achievement of disease remission. The aim of this study was to identify the risk factors for infection, with a focus on the dose of glucocorticoids administered, following the achievement of disease remission in rheumatic diseases patients. We retrospectively analyzed the medical records of rheumatic disease patients who had been treated with glucocorticoids. The primary endpoint was the incidence rate of infection during a period from 1 to 2 months after the commencement of treatment. From April 2006 to March 2010, 19 of 92 patients suffered from infection during the observation period. Age >= 65 yrs, presence of interstitial pneumonia, diagnosis of systemic vasculitis and serum creatinine level >= 2.0 mg/dl were found to be univariate predictors for infection. However, only the presence of interstitial pneumonia was an independent risk factor for infection (HR = 4.50, 95% CI = 1.65 to 14.44) by the Cox proportional hazard model. Even after achievement of clinical remission, careful observation is needed for patients with interstitial pneumonia, more so than for those receiving high-dose glucocorticoids.

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  • Functional interaction of bone morphogenetic protein and growth hormone releasing peptide in adrenocorticotropin regulation by corticotrope cells

    Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Kenichi Inagaki, Eri Nakamura, Tomohiro Terasaka, Masaya Takeda, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

    MOLECULAR AND CELLULAR ENDOCRINOLOGY   344 ( 1-2 )   41 - 50   2011年9月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Mechanisms by which GHRP stimulates ACTH release in corticotrope cells were investigated using mouse corticotrope AtT20 cells by focusing on the biological activity of BMP-4. GHRP-2 increased ACTH and cAMP secretion by AtT20 cells; however, its effects were less potent than the effects of CRH. BMP-4 suppressed basal ACTH production and POMC transcription, and the inhibition of endogenous BMP receptor signaling led to an increase in ACTH production. Of note, BMP-4 suppressed ACTH production and POMC-promoter activity induced by CRH more efficaciously than that induced by GHRP-2. BMP-4 had no significant effect on cAMP synthesis induced by CRH or GHRP-2. Stimulation with CRH, but not GHRP-2, activated ERK1/2, p38, SAPK/JNK and Akt phosphorylation, in which CRH-induced phosphorylation of ERR and p38 was suppressed by BMP-4. GHRP-2-induced ACTH secretion was not affected by inhibitors of ERR, p38 and Akt pathways, which effectively suppressed CRH-induced ACTH release. Blockage of the cAMP-PKA pathway reversed CRH- as well as GHRP-2-induced ACTH secretion. Furthermore, the inhibition of ERR and p38 significantly reduced cAMP synthesis induced by CRH but not by GHRP-2. Thus, CRH activates ACTH production through ERR and p38 pathways in addition to the cAMP-PKA pathway, which is also activated downstream of MAPK. On the other hand, GHRP-2-induced ACTH production was predominantly linked to the cAMP-PKA pathway. Moreover, CRH and GHRP-2 upregulated BMP receptor signaling, while BMP-4, CRH and GHRP-2 had no significant effect on the expression level of GHSR. In addition, GHRP-2 suppressed the expression of Smad7, which is an inhibitor of the BMP-Smad1/5/8 pathway. Collectively, the results revealed a functional interaction between GHRP-2 and BMP signaling, in which endogenous BMP may act as an autoregulatory system in controlling ACTH production. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

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  • Japan Renal Biopsy Registry: the first nationwide, web-based, and prospective registry system of renal biopsies in Japan

    Hitoshi Sugiyama, Hitoshi Yokoyama, Hiroshi Sato, Takao Saito, Yukimasa Kohda, Shinichi Nishi, Kazuhiko Tsuruya, Hideyasu Kiyomoto, Hiroyuki Iida, Tamaki Sasaki, Makoto Higuchi, Motoshi Hattori, Kazumasa Oka, Shoji Kagami, Michio Nagata, Tetsuya Kawamura, Masataka Honda, Yuichiro Fukasawa, Atsushi Fukatsu, Kunio Morozumi, Norishige Yoshikawa, Yukio Yuzawa, Seiichi Matsuo, Yutaka Kiyohara, Kensuke Joh, Takashi Taguchi, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   15 ( 4 )   493 - 503   2011年8月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Background The Committee for the Standardization of Renal Pathological Diagnosis and the Working Group for Renal Biopsy Database of the Japanese Society of Nephrology started the first nationwide, web-based, and prospective registry system, the Japan Renal Biopsy Registry (J-RBR), to record the pathological, clinical, and laboratory data of renal biopsies in 2007.
    Methods The patient data including age, gender, laboratory data, and clinical and pathological diagnoses were recorded on the web page of the J-RBR, which utilizes the system of the Internet Data and Information Center for Medical Research in the University Hospital Medical Information Network. We analyzed the clinical and pathological diagnoses registered on the J-RBR in 2007 and 2008.
    Results Data were collected from 818 patients from 18 centers in 2007 and 1582 patients from 23 centers in 2008, including the affiliated hospitals. Renal biopsies were obtained from 726 native kidneys (88.8%) and 92 renal grafts (11.2%) in 2007, and 1400 native kidneys (88.5%) and 182 renal grafts (11.5%) in 2008. The most common clinical diagnosis was chronic nephritic syndrome (47.4%), followed by nephrotic syndrome (16.8%) and renal transplantation (11.2%) in 2007. A similar frequency of the clinical diagnoses was recognized in 2008. Of the native kidneys, the most frequent pathological diagnosis as classified by pathogenesis was immunoglobulin (Ig) A nephropathy (IgAN) both in 2007 (32.9%) and 2008 (30.2%). Among the primary glomerular diseases (except IgAN), membranous nephropathy (MN) was the most common disease both in 2007 (31.4%) and 2008 (25.7%).
    Conclusions In a cross-sectional study, the J-RBR has shown IgAN to be the most common disease in renal biopsies in 2007 and 2008, consistent with previous Japanese studies. MN predominated in the primary glomerular diseases (except for IgAN). The frequency of the disease and the clinical and demographic correlations should be investigated in further analyses by the J-RBR.

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  • Involvement of MAPKs in ICAM-1 Expression in Glomerular Endothelial Cells in Diabetic Nephropathy

    Naomi Watanabe, Kenichi Shikata, Yasushi Shikata, Kei Sarai, Kazuyoshi Omori, Ryo Kodera, Chikage Sato, Jun Wada, Hirofumi Makino

    ACTA MEDICA OKAYAMA   65 ( 4 )   247 - 257   2011年8月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Inflammatory processes are involved in the pathogenesis of diabetic nephropathy. The aim of this study was to clarify the role of mitogen-activated protein kinase (MAPK) pathways for induction of intercellular adhesion molecule-1 (ICAM-1) expression in glomerular endothelial cells under diabetic conditions. We examined the expression of ICAM-1 in the kidneys of experimental diabetic rats. Human glomerular endothelial cells (GE cells) were exposed to normal glucose concentration, high glucose concentration (HG), or high mannitol concentration (HM), and then the expression of the ICAM-1 protein and the phosphorylation of the 3 subfamilies of mitogen-activated protein kinase (MAPK) were determined using Western blot analysis. Next, to evaluate the involvement of MAPKs in HG- or HM-induced ICAM-1 expression, we preincubated GE cells with the inhibitors for ERK, p38 or JNK 1h prior to the application of glucose or mannitol. Expression of ICAM-1 was increased in the glomeruli of diabetic rats. Both FIG and HM induced ICAM-1 expression and phosphorylation of ERK1/2, p38 and JINX in GE cells. Expression of ICAM-1 was significantly attenuated by inhibitors of ERK, p38 and JNK. We conclude that activation of ERK1/2, p38 and JNK cascades may be involved in ICAM-1 expression in glomerular endothelial cells under diabetic conditions.

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  • Functional interaction of fibroblast growth factor-8, bone morphogenetic protein and estrogen receptor in breast cancer cell proliferation

    Hiroko Masuda, Fumio Otsuka, Yoshinori Matsumoto, Mariko Takano, Tomoko Miyoshi, Kenichi Inagaki, Tadahiko Shien, Naruto Taira, Hirofumi Makino, Hiroyoshi Doihara

    MOLECULAR AND CELLULAR ENDOCRINOLOGY   343 ( 1-2 )   7 - 17   2011年8月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Estrogen is involved in the development and progression of breast cancer. Here we investigated the effect of fibroblast growth factor (FGF)-8 on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptor (ER)alpha, ER beta, FGF receptors, and Smad signaling molecules. Estradiol stimulated MCF-7 cell proliferation in a concentration-responsive manner, whereas BSA-bound estradiol had a weak effect on MCF-7 cell mitosis compared with the effect of free estradiol. It is notable that estrogen-induced cell proliferation was enhanced in the presence of FGF-8 and that the combined effects were reversed in the presence of an FGF-receptor kinase inhibitor or an ER antagonist. It was also revealed that FGF-8 increased the expression levels of ER alpha, ER beta and aromatase mRNAs, while estradiol reduced the expression levels of ERs, aromatase and steroid sulfatase in MCF-7 cells. FGF-8-induced phosphorylation of FGF receptors was augmented by estradiol, which was reversed by an ER antagonist. FGF-8-induced activation of MAPKs and AKT signaling was also upregulated in the presence of estrogen. On the other hand, FGF-8 suppressed BMP-7 actions that are linked to mitotic inhibition by activating the cell cycle regulator cdc2. FGF-8 was revealed to inhibit BMP receptor actions including Id-1 promoter activity and Smad1/5/8 phosphorylation by suppressing expression of BMP type-II receptors and by increasing expression of inhibitory Smads. Collectively, the results indicate that FGF-8 acts to facilitate cell proliferation by upregulating endogenous estrogenic actions as well as by suppressing BMP receptor signaling in ER-expressing breast cancer cells. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

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  • Rhabdomyosarcoma discovered in the adrenal region of an elderly hypertensive patient

    Akihiro Katayama, Fumio Otsuka, Masaya Takeda, Tomoko Miyoshi, Eri Nakamura, Kenichi Inagaki, Takehiro Tanaka, Shinya Uehara, Hirofumi Makino

    HYPERTENSION RESEARCH   34 ( 6 )   784 - 786   2011年6月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

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  • Icodextrin Increases Technique Survival Rate in Peritoneal Dialysis Patients with Diabetic Nephropathy by Improving Body Fluid Management: A Randomized Controlled Trial

    Yuji Takatori, Shigeru Akagi, Hitoshi Sugiyama, Junko Inoue, Shoichiro Kojo, Hiroshi Morinaga, Kazushi Nakao, Jun Wada, Hirofumi Makino

    CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   6 ( 6 )   1337 - 1344   2011年6月

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    記述言語:英語   出版者・発行元:AMER SOC NEPHROLOGY  

    Background and objectives There are still controversies whether peritoneal dialysis (PD) with icodextrin preserves residual renal and peritoneal membrane functions in patients with diabetes. However, there are no randomized controlled and long-term clinical trials in newly started PD patients with diabetic nephropathy.
    Design, setting, participants, & measurements Forty-one patients with diabetic nephropathy with ESRD were enrolled and randomly assigned to the glucose group (GLU) treated with 8 L of 1.5% or 2.5% glucose or an icodextrin group (ICO) treated with 1.5 or 2.0 L of 7.5% icodextrin-containing solutions. Technique failure, body fluid management, glucose and lipid metabolism, and residual renal and peritoneal functions and were evaluated over 2 years.
    Results The technique survival rate was 71.4% in ICo and 45.0% in GLU, with most of the technique failure due to volume overload. ICO showed significantly better cumulative technique survival. Net ultrafiltration volume was significantly higher in ICO throughout the study period. There were no beneficial effects of icodextrin on hemoglobin A1c, glycoalbumin, and lipid profile at 24 months. Urine volume and residual renal function declined faster in ICO, but there were no significant differences between the two groups. For peritoneal function, no differences were observed in dialysis-to-plasma creatinine ratios during the observation.
    Conclusions In PD therapy for diabetic nephropathy, the use of icodextrin-containing solutions has a beneficial effect on technique survival, but there are no apparent benefits or disadvantages in residual renal and peritoneal functions compared with conventional PD with glucose solution. Clin J An, Soc Nephrol 6: 1337-1344, 2011. doi: 10.2215/CJN.10041110

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  • Unexpected occurrence of adrenal Cushing's syndrome in a patient with systemic lupus erythematosus

    Akihiro Katayama, Fumio Otsuka, Katsuyuki Tanabe, Naoko Tsukamoto, Ryutaro Yamanaka, Yoshinori Matsumoto, Yasutomo Nasu, Hirofumi Makino

    HYPERTENSION RESEARCH   34 ( 5 )   662 - 663   2011年5月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

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  • The relation between estimated glomerular filtration rate and proteinuria in Okayama Prefecture, Japan

    Nobuyuki Miyatake, Kenichi Shikata, Hirofumi Makino, Takeyuki Numata

    Environmental Health and Preventive Medicine   16 ( 3 )   191 - 195   2011年5月

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    記述言語:英語  

    Objective We investigated the link between renal function as evaluated by estimated glomerular filtration rate (eGFR) and proteinuria in Okayama Prefecture, Japan. Subjects and methods A total of 11030 Japanese subjects, aged between 20 and 79 years, were recruited in a crosssectional clinical investigation study. eGFR was calculated using serum creatinine, age, and sex. Proteinuria was measured by using urine strip devices. Results Age-related variations in eGFR were noted. Two hundred sixteen men (6.2%) and 316 women (4.2%) were diagnosed with trace positive (±) and 140 men (4.0%) and 130 women (1.7%) were diagnosed with positive (?B) proteinuria. eGFR in subjects with ?B proteinuria was significantly lower than that in subjects without proteinuria, in both sexes. Conclusion The present study indicates that proteinuria might be an important marker in the etiology of lower eGFR in Okayama Prefecture, Japan. © 2010 The Japanese Society for Hygiene.

    DOI: 10.1007/s12199-010-0183-9

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  • Emphysematous Cystitis in a Patient with Type 2 Diabetes Mellitus

    Noriko Toyota, Daisuke Ogawa, Keita Ishii, Kyoji Hirata, Jun Wada, Kenichi Shikata, Hirofumi Makino

    ACTA MEDICA OKAYAMA   65 ( 2 )   129 - 133   2011年4月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    A 62-year-old woman with a history of poorly controlled type 2 diabetes mellitus was admitted to our hospital with a 3-week history of mild fever, vomiting, and anorexia. Abdominal computed tomography (CT) showed bilateral hydronephrosis and gas accumulation in the urinary bladder wall and left ureter. Laboratory tests showed leukocytosis and elevated C-reactive protein level. Urine culture showed heavy growth of Escherichia coli. The final diagnosis was emphysematous cystitis. The patient was treated with systemic antibiotics and drainage using a urethral catheter. The clinical and radiographic findings resolved rapidly, and she was discharged from the hospital on day 28. Emphysematous cystitis is a relatively rare urinary tract infection associated with gas formation, and has the potential for a serious outcome if untreated. Early detection by imaging studies such as CT is important in providing prompt treatment and favorable clinical outcome.

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  • Intercellular adhesion molecule-1 plays a critical role in glomerulosclerosis after subtotal nephrectomy

    Yuichi Kido, Daisuke Ogawa, Kenichi Shikata, Motofumi Sasaki, Ryo Nagase, Shinichi Okada, Hitomi Usui Kataoka, Jun Wada, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   15 ( 2 )   212 - 219   2011年4月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Hyperfiltration in the glomeruli have been considered to be an important cause of glomerular injury; however, the role of intercellular adhesion molecule (ICAM)-1 in the pathogenesis of glomerulosclerosis is not known.
    To elucidate the effects of ICAM-1 depletion on hyperfiltration-induced glomerular disorder, we used subtotally nephrectomized ICAM-1(+/+) and ICAM-1(-/-) mice. We evaluated macrophage infiltration, mesangial matrix expansion, transforming growth factor (TGF)-beta and type IV collagen accumulation in glomeruli.
    Macrophage infiltration into the glomeruli and mesangial matrix expansion coincident with increased expression of both ICAM-1 and TGF-beta, and accumulation of type IV collagen were ameliorated in subtotally nephrectomized ICAM-1(-/-) mice compared to ICAM-1(+/+) mice. ICAM-1 depletion significantly reduced hyperfiltration-induced glomerular injury after renal ablation.
    Our present findings suggest that glomerular hyperfiltration is the leading cause of glomerulosclerosis, and it is mediated, at least in part, by ICAM-1 expression and macrophage infiltration.

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  • Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis

    Daisuke Saito, Yohei Maeshima, Tatsuyo Nasu, Hiroko Yamasaki, Katsuyuki Tanabe, Hitoshi Sugiyama, Hikaru Sonoda, Yasufumi Sato, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY   300 ( 4 )   F873 - F886   2011年4月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Saito D, Maeshima Y, Nasu T, Yamasaki H, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis. Am J Physiol Renal Physiol 300: F873-F886, 2011. First published January 12, 2011; doi:10.1152/ajprenal.00503.2010.-The involvement of VEGF-A as well as the therapeutic efficacy of angiogenesis inhibitors in diabetic nephropathy have been reported. We recently reported the therapeutic effects of vasohibin-1 (VASH-1), an endogenous angiogenesis inhibitor, in a type 1 diabetic nephropathy model (Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H. Diabetes 58: 2365-2375, 2009). In this study, we investigated the therapeutic efficacy of VASH-1 on renal alterations in obese mice with type 2 diabetes. Diabetic db/db mice received intravenous injections of adenoviral vectors encoding human VASH-1 (AdhVASH-1) and were euthanized 8 wk later. AdhVASH-1 treatment resulted in significant suppression of glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase in the CD31(+) glomerular endothelial area, F4/80(+) monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix. An increase in the renal levels of VEGF-A, VEGFR-2, transforming growth factor (TGF)-beta 1, and monocyte chemoattractant protein-1 in diabetic animals was significantly suppressed by AdhVASH-1 (immunoblotting). AdhVASH-1 treatment significantly recovered the loss and altered the distribution patterns of nephrin and zonula occludens (ZO)-1 and suppressed the increase in the number of fibroblast-specific protein-1 (FSP-1(+)) and desmin(+) podocytes in diabetic mice. In vitro, recombinant human VASH-1 (rhVASH-1) dose dependently suppressed the upregulation of VEGF induced by high ambient glucose (25 mM) in cultured mouse podocytes. In addition, rhVASH-1 significantly recovered the mRNA levels of nephrin and the protein levels of ZO-1 and P-cadherin and suppressed the increase in protein levels of desmin, FSP-1, Snail, and Slug in podocytes under high-glucose condition. Taken together, these results suggest the potential use of VASH-1 as a novel therapeutic agent in type 2 diabetic nephropathy mediated via antiangiogenic effects and maintenance of podocyte phenotype in association with antiproteinuric effects.

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  • The Macrophage Is a Key Factor in Renal Injuries Caused by Glomerular Hyperfiltration

    Motofumi Sasaki, Kenichi Shikata, Shinichi Okada, Satoshi Miyamoto, Shingo Nishishita, Hitomi Usui Kataoka, Chikage Sato, Jun Wada, Daisuke Ogawa, Hirofumi Makino

    ACTA MEDICA OKAYAMA   65 ( 2 )   81 - 89   2011年4月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Glomerular hyperfiltration is a common pathway leading to glomerulosclerosis in various kinds of kidney diseases. The 5/6 renal ablation is an established experimental animal model for glomerular hyperfiltration. On the other hand, low-grade inflammation is also a common mechanism for the progression of kidney diseases including diabetic nephropathy and atherosclerosis. Here we analyzed the gene expression profile in the remnant kidney tissues of 5/6 nephrectomized mice using a DNA microarmy system and compared it with that of sham-operated control mice. The 5/6 nephrectomized mice showed glomerular hypertrophy and an increase in the extracellular matrix in the glomeruli. DNA microarray analysis indicated the up-regulated expression of various kinds of genes related to the inflammatory process in remnant kidneys. We confirmed the up-regulated expression of platelet factor-4, and monocyte chemoattractant protein-1, 2, and 5 in remnant kidneys by RT-PCR. The current results; suggest that the inflammatory process is involved in the progression of glomerulosclerosis and is a common pathway of the pathogenesis of kidney disease.

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  • Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes

    R. Kodera, K. Shikata, H. U. Kataoka, T. Takatsuka, S. Miyamoto, M. Sasaki, N. Kajitani, S. Nishishita, K. Sarai, D. Hirota, C. Sato, D. Ogawa, H. Makino

    DIABETOLOGIA   54 ( 4 )   965 - 978   2011年4月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose.
    We administered exendin-4 at 10 mu g/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro.
    Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-kappa B activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells.
    These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue.

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  • Management of anemia in chronic kidney disease patients: baseline findings from Chronic Kidney Disease Japan Cohort Study

    Tadao Akizawa, Hirofumi Makino, Seiichi Matsuo, Tsuyoshi Watanabe, Enyu Imai, Kosaku Nitta, Yasuo Ohashi, Akira Hishida

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   15 ( 2 )   248 - 257   2011年4月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Anemia is a factor that affects the outcome of patients with chronic kidney disease (CKD); however, there are only a few reports on the management of anemia in Japanese patients with CKD who are not on dialysis.
    We investigated the prevalence, related factors and management of anemia in CKD stage 3-5 patients in Japan based on the baseline data obtained from a prospective cohort study (Chronic Kidney Disease Japan Cohort). Anemia was defined as having a hemoglobin (Hb) level of < 11 g/dL or receiving erythropoiesis stimulating agent (ESA) therapy.
    The result indicated that 946 out of 2,930 patients had anemia. Of these 946 patients, 385 were receiving ESA treatment for anemia and had an Hb level of 10.28 +/- A 1.19 g/dL (mean +/- A SD). The percentage of these patients with an Hb level above the target of 11 g/dL proposed for treatment by the Japanese guidelines, and above the maintenance level of 10 g/dL approved for ESA therapy in Japan, was only 30.1 and 61.6%, respectively. In contrast, the percentage of patients receiving no ESA therapy was 67.6 and 55.7%, respectively, among those with an Hb level of < 11 and < 10 g/dL.
    These data suggested that prevalence of anemia was high in Japanese patients with CKD stage 3-5, that the percentage of patients receiving ESA was low among those who required ESA, and that a large number of patients receiving ESA failed to maintain the recommended level of Hb.

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  • Effects of eplerenone on nephrotic syndrome in a patient with renovascular hypertension

    Jiro Suzuki, Fumio Otsuka, Kenichi Inagaki, Katsuyuki Tanabe, Naoko Tsukamoto, Tomoko Miyoshi, Eri Nakamura, Toshio Ogura, Isao Kumagai, Hirofumi Makino

    HYPERTENSION RESEARCH   34 ( 3 )   404 - 406   2011年3月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

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  • Intermittent administration of a sustained-release prostacyclin analog ONO-1301 ameliorates renal alterations in a rat type 1 diabetes model

    H. Yamasaki, Y. Maeshima, T. Nasu, D. Saito, K. Tanabe, K. Hirokoshi-Kawahara, H. Sugiyama, Y. Sakai, H. Makino

    PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS   84 ( 3-4 )   99 - 107   2011年3月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI LTD  

    Diabetic nephropathy is the most common pathological disorder predisposing end-stage renal disease. ONO-1301 is a novel sustained-release prostacyclin analog possessing thromboxane (T)() synthase inhibitory activity. Here, we aimed to investigate the therapeutic efficacies of ONO-1301 in a rat type 1 diabetic nephropathy model. Streptozotocin (STZ)-induced diabetic rats received injections of slow-release form of ONO-1301 (SR-ONO) every 3 weeks. Animals were sacrificed at Week 14. SR-ONO significantly suppressed albuminuria, glomerular hypertrophy, mesangial matrix accumulation, glomerular accumulation of monocyte/macrophage, increase in glomerular levels of pro-fibrotic factor transforming growth factor (TGF)-beta1 and the number of glomerular alpha-smooth muscle actin (SMA). cells in diabetic animals. The glomerular levels of hepatocyte growth factor (HGF) were significantly increased in SR-ONO-treated diabetic animals. Taken together, these results suggest the potential therapeutic efficacy of intermittent administration of SR-ONO in treating diabetic nephropathy potentially via inducing HGF, thus counteracting the pro-fibrotic effects of TGF-beta1. (C) 2010 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.plefa.2010.11.005

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  • Activation of peroxisome proliferator-activated receptor σ inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice.

    Matsushita Y, Ogawa D, Wada J, Yamamoto N, Shikata K, Sato C, Tachibana H, Toyota N, Makino H

    Diabetes   60 ( 3 )   960 - 968   2011年3月

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  • Activities of bone morphogenetic proteins in prolactin regulation by somatostatin analogs in rat pituitary GH3 cells

    Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Kenichi Inagaki, En I. Nakamura, Jiro Suzuki, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

    MOLECULAR AND CELLULAR ENDOCRINOLOGY   332 ( 1-2 )   163 - 169   2011年1月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Involvement of the pituitary BMP system in the modulation of prolactin (PRL) secretion regulated by somatostatin analogs, including octreotide (OCT) and pasireotide (SOM230), and a dopamine agonist, bromocriptine (BRC), was examined in GH3 cells. GH3 cells are rat pituitary somato-lactotrope tumor cells that express somatostatin receptors (SSTRs) and BMP system molecules including BMP-4 and -6. Treatment with BMP-4 and -6 increased PRL and cAMP secretion by GH3 cells. The BMP-4 effects were neutralized by adding a BMP-binding protein Noggin. These findings suggest the activity of endogenous BMPs in augmenting PRL secretion by GH3 cells. BRC and SOM230 reduced PRL secretion, but OCT failed to reduce the PRL level. In GH3 cells activated by forskolin, BRC suppressed forskolin-induced PRL secretion with reduction in cAMP levels. OCT did not affect forskolin-induced PRL level, while SOM230 reduced PRL secretion and PRL mRNA expression induced by forskolin. BMP-4 treatment enhanced the reducing effect of SOM230 on forskolin-induced PRL level while BMP-4 did not affect the effects of OCT or BRC. Noggin treatment had no significant effect on the BRC actions reducing PRL levels by GH3 cells. However, in the presence of Noggin, OCT elicited an inhibitory effect on forskolin-induced PRL secretion and PRL mRNA expression, whereas the SOM230 effect on PRL reduction was in turn impaired. It was further found that BMP-4 and -6 suppressed SSTR-2 but increased SSTR-5 mRNA expression of GH3 cells. These findings indicate that Noggin rescues SSTR-2 but downregulates SSTR-5 by neutralizing endogenous BMP actions, leading to an increase in OCT sensitivity and a decrease in SOM230 sensitivity of GH3 cells. In addition, BMP signaling was facilitated in GH3 cells treated with forskolin. Collectively, these findings suggest that BMPs elicit differential actions in the regulation of PRL release dependent on cellular cAMP-PKA activity. BMPs may play a key role in the modulation of SSTR sensitivity of somato-lactotrope cells in an autocrine/paracrine manner. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.mce.2010.10.008

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  • P-Selectin Glycoprotein Ligand-1 Deficiency Is Protective Against Obesity-Related Insulin Resistance

    Chikage Sato, Kenichi Shikata, Daisho Hirota, Motofumi Sasaki, Shingo Nishishita, Satoshi Miyamoto, Ryo Kodera, Daisuke Ogawa, Atsuhito Tone, Hitomi Usui Kataoka, Jun Wada, Nobuo Kajitani, Hirofumi Makino

    DIABETES   60 ( 1 )   189 - 199   2011年1月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    OBJECTIVE An inflammatory process is involved in the mechanism of obesity-related insulin resistance. Recent studies indicate that monocyte chemoattractant protein-1 (MCP-1) is a major chemokine that promotes monocyte infiltration into adipose tissues; however, the adhesion pathway in adipose tissues remains unclear. We aimed to clarify the adhesion molecules that mediate monocyte infiltration into adipose tissue.
    RESEARCH DESIGN AND METHODS We used a DNA microarray to compare the gene expression profiles in epididymal white adipose tissues (eWAT) between db/db mice and C57/BL6 mice each fed a high-fat diet (HFD) or a low-fat diet (LFD). We investigated the change of insulin resistance and inflammation in eWAT in P-selectin glycoprotein ligand-1 (PSGL-1) homozygous knockout (PSGL-1(-/-)) mice compared with wild-type (WT) mice fed HFD.
    RESULTS DNA microarray analysis revealed that PSGL-1, a major ligand for selectins, is upregulated in eWAT from both db/db mice and WT mice fed HFD. Quantitative real-time RT-PCR and immunohistochemistry showed that PSGL-1 is expressed on both endothelial cells and macrophages in eWAT of obese mice. PSGL-1-/- mice fed HFD showed a remarkable reduction of macrophage accumulation and expression of proinflammatory genes, including MCP-1 in eWAT. Moreover, adipocyte hypertrophy, insulin resistance, lipid metabolism, and hepatic fatty change were improved in PSGL-1-/- mice compared with WT mice fed HFD.
    CONCLUSIONS These results indicate that PSGL-1 is a crucial adhesion molecule for the recruitment of monocytes into adipose tissues in obese mice, making it a candidate for a novel therapeutic target for the prevention of obesity-related insulin resistance. Diabetes 60:189-199, 2011

    DOI: 10.2337/db09-1894

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  • 糖尿病性腎症の発症と進展に対する血圧・メタボリックリスクの影響.

    小川大輔, 槇野博史

    Diabetes Frontier   22 ( 5 )   484 - 488   2011年

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  • Serum high sensitivity cardiac troponin T is a significant biomarker of left ventricular diastolic dysfunction in subjects with non-diabetic chronic kidney disease. 国際誌

    Kitagawa M, Sugiyama H, Morinaga H, Inoue T, Takiue K, Kikumoto Y, Uchida HA, Kitamura S, Maeshima Y, Toh N, Nakamura K, Ito H, Makino H

    Nephron Extra   1 ( 1 )   166 - 177   2011年

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    記述言語:英語  

    DOI: 10.1159/000333801

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  • Comparison of ventilator threshold between subjects with and without proteinuria in Japanese.

    Miyatake N, Shikata K, Makino H, Numata T

    Health   3 ( 6 )   394 - 399   2011年

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  • Decreasing serum uric acid levels might be associated with improving estimated glomerular filtration rate(eGFR) in Japanese men.

    Miyatake N, Shikata K, Makino H, Numata T

    Health   3 ( 8 )   498 - 503   2011年

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  • 抗甲状腺薬により劇症肝炎をきたし肝移植にて救命しえた一例.

    塚本尚子, 大塚文男, 鈴木二郎, 武田昌也, 稲垣兼一, 小倉可奈子, 中村絵里, 三好智子, 三村由香里, 小倉俊郎, 元木崇之, 槇野博史

    日本内分泌学会雑誌   87   35 - 37   2011年

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  • Abnormalities of glycogens in tonsillar lymphocytes in IgA nephropathy.

    Inoue T, Sugiyama H, Kitagawa M, Takiue K, Morinaga H, Kikumoto Y, Maeshima Y, Fukushima K, Nishizaki K, Akagi H, Hiki Y, Makino H

    Adv Otorhinolaryngol   72   71 - 74   2011年

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  • Diabetic lipemiaa ssociated with acute pancreatitis in a patient with type 2 diabetes.

    Ogawa D, Wada J, Makino H

    Journal of Diabetes Mellitus   1 ( 3 )   54 - 56   2011年

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  • The relation between estimated glomerular filtration rate(eGFR)and consumption in the japanese.

    Miyatake N, Shikata K, Makino H, Numata T

    Health   3 ( 9 )   549 - 552   2011年

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  • High Glucose Increases Metallothionein Expression in Renal Proximal Tubular Epithelial Cells

    Daisuke Ogawa, Masato Asanuma, Ikuko Miyazaki, Hiromi Tachibana, Jun Wada, Norio Sogawa, Takeshi Sugaya, Shinji Kitamura, Yohei Maeshima, Kenichi Shikata, Hirofumi Makino

    EXPERIMENTAL DIABETES RESEARCH   2011   534872 - 534872   2011年

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    記述言語:英語   出版者・発行元:HINDAWI PUBLISHING CORPORATION  

    Metallothionein(MT) is an intracellular metal-binding, cysteine-rich protein, and is a potent antioxidant that protects cells and tissues from oxidative stress. Although the major isoforms MT-1 and -2 (MT-1/-2) are highly inducible in many tissues, the distribution and role of MT-1/-2 in diabetic nephropathy are poorly understood. In this study, diabetes was induced in adult male rats by streptozotocin, and renal tissues were stained with antibodies for MT-1/-2. MT-1/-2 expression was also evaluated in mProx24 cells, a mouse renal proximal tubular epithelial cell line, stimulated with high glucose medium and pretreated with the antioxidant vitamin E. MT-1/-2 expression was gradually and dramatically increased, mainly in the proximal tubular epithelial cells and to a lesser extent in the podocytes in diabetic rats, but was hardly observed in control rats. MT-1/-2 expression was also increased by high glucose stimulation in mProx24 cells. Because the induction of MT was suppressed by pretreatment with vitamin E, the expression of MT-1/-2 is induced, at least in part, by high glucose-induced oxidative stress. These observations suggest that MT-1/-2 is induced in renal proximal tubular epithelial cells as an antioxidant to protect the kidney from oxidative stress, and may offer a novel therapeutic target against diabetic nephropathy.

    DOI: 10.1155/2011/534872

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  • 血栓性血小板減少性紫斑病を生じたクッシング症候群の1例.

    大塚文男, 瀧上慶一, 氏家はる代, 稲垣兼一, 三好智子, 武田昌也, 塚本尚子, 中村絵里, 三村由香里, 小倉俊郎, 槇野博史

    ACTH Related Peptides   22   80 - 81   2011年

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  • Systemic Lupus Erythematosus Complicated with Acute Myocardial Infarction and Ischemic Colitis

    Yoshinori Matsumoto, Hiroshi Wakabayashi, Fumio Otsuka, Kentaro Inoue, Mariko Takano, Ken-ei Sada, Hirofumi Makino

    INTERNAL MEDICINE   50 ( 21 )   2669 - 2673   2011年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Acute myocardial infarction (AMI) is one of the most severe manifestations in patients with systemic lupus erythematosus (SLE). Ischemic colitis, mainly caused by intestinal vasculitis, is also one of the most serious, but uncommon, complications in SLE patients. "SLE vasculitis" simultaneously involving cardiac and gastrointestinal vessels has yet to be reported. This is the first report of SLE accompanying AMI, ischemic colitis and perforation of the digestive tract possibly due to SLE vasculitis, which was dramatically improved by treatment with high-dose glucocorticoid.

    DOI: 10.2169/internalmedicine.50.5966

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  • Comparison of muscle strength between subjects with and without proteinuria.

    Miyatake N, Shikata K, Makino H, Numata T

    Health   3 ( 11 )   698 - 702   2011年

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  • ソマトトロープ細胞におけるBMP-4によるSSTR感受性の調節機序の検討.

    大塚文男, 塚本尚子, 三好智子, 中村絵里, 鈴木二郎, 稲垣兼一, 槇野博史

    第6回アクロメガリーフォーラム記録集   6 - 6   2011年

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  • コレステロール塞栓症とAKI.

    内田治仁, 槇野博史

    内科系総合雑誌ModernPhysician   31 ( 1 )   53 - 56   2011年

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  • メタボリックシンドロームに起因もしくは関連する病態とその管理 慢性腎臓病.

    片山晶博, 和田 淳, 槇野博史

    メタボリックシンドローム(第2版)-基礎・臨床の最新知見-   69 ( 1 )   410 - 415   2011年

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  • 腎症の血圧管理は?糖尿病性腎症の血圧管理目標値について教えて下さい.

    橘 洋美, 和田 淳, 槇野博史

    肥満と糖尿病   10 ( 1 )   72 - 75   2011年

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  • 糖尿病における腎臓病・CKDの診断・検査法.

    小川大輔, 槇野博史

    心血管リスクを防ぐ!糖尿病診療ガイド   145 - 148   2011年

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  • ANCA関連血管炎の診療ガイドライン.

    尾崎承一, 槇野博史, 松尾清一

    厚生労働省難治性疾患克服研究事業   1 - 94   2011年

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  • ANCA関連血管炎―臓器別にみた最近の話題 はじめに.

    槇野博史

    医学の歩み   236 ( 8 )   759 - 759   2011年

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  • わが国の難治性血管炎研究の現況過去から未来へRemIT-JAV研究わが国のANCA関連血管炎の診察実態の把握を目指して.

    山村昌弘, 佐田憲映, 針谷正祥, 藤井隆夫, 有村義宏, 槇野博史

    脈管学   51 ( 1 )   79 - 85   2011年

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  • アミロイドーシス.

    木野村賢, 杉山 斉, 槇野博史

    病気と薬パーフェクトBOOK 2011   62 ( 4 )   862 - 865   2011年

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  • 難治性内科疾患の克服に向けて ANCA関連血管炎の診断と治療の現況.

    槇野博史, 佐田憲映

    日本内科学会雑誌   100 ( 3 )   668 - 672   2011年

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  • 序文.

    槇野博史

    皮膚症状からみた血管炎診断の手引き   3 - 3   2011年

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  • 尿蛋白.

    菊本陽子, 杉山 斉, 槇野博史

    臨床検査ガイド   928 - 933   2011年

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  • 7.ANCA関連血管炎の診断と治療の現況.

    槇野博史, 佐田憲映

    日本内科学会雑誌   100 ( 3 )   668 - 672   2011年

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  • 厚生労働省特定疾患進行性腎障害に関する調査研究班報告 急速進行性腎炎症候群の診療指針(第2版).

    松尾清一, 山縣邦弘, 槇野博史, 有村義宏, 武曾恵理, 新田孝作, 和田隆志, 田熊淑男, 小林正貴, 堀越哲, 細谷龍男, 湯澤由紀夫, 渡辺毅, 藤元昭一, 平和伸仁, 木村健二郎, 湯村和子, 伊藤孝史, 佐田憲映, 板橋美津世, 古市賢吾, 佐藤壽伸, 木村朋由, 平山浩一, 宇都宮保典, 冨永直人, 斎藤知栄, 臼井丈一, 横山仁, 田口尚, 川村哲也, 今井圓裕, 斉藤喬雄, 成田一衛

    日本腎臓学会誌   53 ( 4 )   509 - 555   2011年

  • 3.肥満症と新たな分泌因子1)Vaspin.

    和田 淳, 勅使川原早苗, 中司敦子, 槇野博史

    日本内科学会誌   100 ( 4 )   996 - 1001   2011年

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  • ミコンビⓇ配合錠AP/BP ミコンビⓇ配合錠の降圧効果と有用性について教えてください.

    小川大輔, 槇野博史

    肥満と糖尿病   10 ( 3 )   247 - 250   2011年

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  • 全身性疾患と腎障害 ANCA関連血管炎の診療ガイドライン.

    山中龍太郎, 佐田憲映, 槇野博史

    綜合臨床   60 ( 6 )   1301 - 1308   2011年

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  • INNOVATION.

    小川大輔, 槇野博史

    高血圧ナビゲーター第3版   212 - 213   2011年

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  • 慢性腎臓病患者の心血管イべントリスク管理におけるストロングスタチンの可能性―自験例の提示を含めて―.

    前島洋平, 斎藤大輔, 槇野博史

    Therapeutic Research   32 ( 6 )   811 - 820   2011年

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  • CKDとその治療管理の歴史とガイドライン.

    綿谷博雪, 前島洋平, 槇野博史

    Medical Practice   28 ( 6 )   972 - 977   2011年

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  • 医療訴訟における「医師の説明」に関する研究.

    福本良之, 槇野博史

    岡山医学会雑誌   123   119 - 127   2011年

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  • 顕微鏡的多発血管炎の重症度の判定と治療指針.

    高野真理子, 佐田憲映, 槇野博史

    Medical Practice   28 ( 7 )   1223 - 1228   2011年

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  • 腹膜透析合同レジストリーとベースライン解析‐多施設共同前向きコホート研究.

    杉山 斉, 伊藤恭彦, 鶴屋和彦, 吉田寿子, 丸山弘樹, 後藤 眞, 中山昌明, 森永裕士, 槇野博史, 松尾清一

    腹膜透析2011.腎と透析   70   251 - 252   2011年

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  • 糖尿病性腎症の現状と課題.

    小川大輔, 槇野博史

    医学のあゆみ   238 ( 9 )   821 - 824   2011年

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  • ディスカッション.

    槇野博史, 片山茂裕, Dick de Zeeuw

    Therapeutic Research   32 ( 9 )   1089 - 1091   2011年

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  • AAVとはなんですか?概念と病型分類を教えて下さい.

    佐田憲映, 槇野博史

    急速進行性糸球体腎炎診療ガイドQ&A   12 - 13   2011年

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  • 早期腎症期の高血圧合併2型糖尿病患者におけるテルミサルタン/アムロジピン併用時の顕性腎症への移行抑制効果―INNOVATION試験追加解析―.

    槇野博史, 伊藤貞嘉, 片山茂裕, 岩本安彦, 河盛隆造, 馬場園哲哉, 守屋達美, 竹内正弘, 羽田勝計

    血圧   18 ( 10 )   1001 - 1008   2011年

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  • 顕微鏡的多発血管炎の腎障害に対する治療.

    木野村賢, 佐田憲映, 槇野博史

    Modem Physician   31 ( 11 )   1385 - 1386   2011年

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  • Insufficient control of morning home blood pressure in Japanese patients with hypertension associated with diabetes mellitus

    Haruhito A. Uchida, Yoshio Nakamura, Hisanao Norii, Masanobu Kaihara, Yoshihisa Hanayama, Ken-Ei Sada, Jun Wada, Kenichi Shikata, Hirofumi Makino

    JOURNAL OF DIABETES INVESTIGATION   1 ( 6 )   266 - 272   2010年12月

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    記述言語:英語   出版者・発行元:WILEY  

    Aims/Introduction: The combination of hypertension with diabetes mellitus (DM) has been recognized as a critical risk factor for cardiovascular disease (CVD). We investigated the blood pressure levels in hypertensive patients with DM (HDM patients) compared with those without DM (HnDM patients). Furthermore, we examined the effect of risk factors, including chronic kidney disease (CKD) and stroke, on the management of both office blood pressure (OBP) and morning home blood pressure (MHBP).
    Materials and Methods: OBP and MHBP were evaluated in 1230 essential hypertensive patients in 30 institutions. Among them, 366 (30%) were complicated with DM.
    Results: The ratio of masked hypertensives whose systolic OBP was < 140 mmHg and systolic MHBP was more than 135 mmHg in HDM patients was significantly higher than that in HnDM patients (P < 0.02). HDM patients had significantly lower systolic and diastolic OBP and diastolic MHBP than HnDM patients (P < 0.05, respectively). However, systolic MHBP in HDM patients tended to be higher compared with HnDM patients (P = 0.0623). A stratified analysis showed that HDM patients with CKD or stroke had significantly higher systolic MHBP than others (P < 0.05, respectively). The adjusted odds ratio for morning hypertension defined by a systolic MHBP more than 135 mmHg was significantly higher in the HDM patients with CKD (1.98) compared with HnDM patients without CKD (reference).
    Conclusions: Diabetes, CKD and stroke are risk factors for MHBP. More intensive treatment is needed to achieve the therapeutic goal for systolic MHBP in HDM patients, especially those who are complicated with CKD or stroke. (J Diabetes Invest, doi:10.1111/j.2040-1124.2010.00056.x, 2010).

    DOI: 10.1111/j.2040-1124.2010.00056.x

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  • A Novel Antagonistic Effect of the Bone Morphogenetic Protein System on Prolactin Actions in Regulating Steroidogenesis by Granulosa Cells

    Eri Nakamura, Fumio Otsuka, Kenichi Inagaki, Tomoko Miyoshi, Ryutaro Yamanaka, Naoko Tsukamoto, Jiro Suzuki, Toshio Ogura, Hirofumi Makino

    ENDOCRINOLOGY   151 ( 11 )   5506 - 5518   2010年11月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    To investigate the mechanism by which prolactin (PRL) regulates follicular steroidogenesis in the ovary, we examined the functional roles of PRL in steroidogenesis using rat oocyte/granulosa cell coculture and focusing on the bone morphogenetic protein (BMP) system. The expression of long and short forms of PRL receptor (PRLR) were detected in both oocytes and granulosa cells, and PRL effectively up-regulated PRLR expression in granulosa cells in the presence of FSH. PRL suppressed FSH-induced estradiol production and increased FSH-induced progesterone production in granulosa cells. The PRL effects on FSH-induced progesterone were blocked by coculture with oocytes, implying roles of oocyte-derived factors in suppression of progesterone production in PRL-exposed granulosa cells. In accordance with the data for steroids, FSH-induced aromatase expression was suppressed by PRL, whereas FSH-induced steroidogenic acute regulatory protein, P450scc (P450 side-chain cleavage enzyme), and 3 beta-hydroxysteroid dehydrogenase type 2 levels were amplified by PRL. However, forskolin-and N(6), O(2)-dibutyryl cAMP-induced steroid levels and FSH- and forskolin-induced cAMP were not affected by PRL, suggesting that PRL action on FSH-induced steroidogenesis was not due to cAMP-protein kinase A regulation. Treatment with a BMP-binding protein, noggin, facilitated PRL-induced estradiol reduction, and noggin increased PRL-induced progesterone production in FSH-treated granulosa cells cocultured with oocytes, suggesting that endogenous BMPs reduce progesterone but increase estradiol when exposed to high concentrations of PRL. PRL increased the expression of BMP ligands in oocyte/granulosa cell coculture and augmented BMP-induced phosphorylated mothers against decapentaplegic 1/5/8 signaling by reducing inhibitory phosphorylated mothers against decapentaplegic 6 expression through the Janus kinase/signal transducer and activator of transcription (STAT) pathway. In addition to STAT activation, PRL enhanced FSH-induced MAPK phosphorylation in granulosa cells, in which ERK activation was preferentially involved in suppression of FSH-induced estradiol. Furthermore, noggin treatment enhanced PRLR signaling including MAPK and STAT. Considering that BMPs suppressed PRLR in granulosa cells, it is likely that the BMP system in growing follicles plays a key role in antagonizing PRLR signaling actions in the ovary exposed to high concentrations of PRL. (Endocrinology 151: 5506-5518, 2010)

    DOI: 10.1210/en.2010-0265

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  • Peramivir for Severe Influenza Infection in a Patient with Diabetic Nephropathy

    Tatsuyo Nasu, Daisuke Ogawa, Jun Wada, Hirofumi Makino

    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE   182 ( 9 )   1209 - 1210   2010年11月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:AMER THORACIC SOC  

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  • Differential expression of glycogenes in tonsillar B lymphocytes in association with proteinuria and renal dysfunction in IgA nephropathy

    Tatsuyuki Inoue, Hitoshi Sugiyama, Yoshiyuki Hiki, Keiichi Takiue, Hiroshi Morinaga, Masashi Kitagawa, Yohei Maeshima, Kunihiro Fukushima, Kazunori Nishizaki, Hirofumi Akagi, Yoshiki Narimatsu, Hisashi Narimatsu, Hirofumi Makino

    CLINICAL IMMUNOLOGY   136 ( 3 )   447 - 455   2010年9月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Aberrant O-glycosylation of serum and tonsillar IgA1 is one of the main pathogeneses of IgA nephropathy (IgAN). However, the synthesis of underglycosylated IgA1 in tonsils has not yet been characterized. This study examined tonsillar B lymphocytes of IgAN (n=34) using tonsils derived from patients with chronic tonsillitis (n=24) and sleep apnea syndrome (n=14) as a control. Gene expression of beta 1,3-galactosyltransferase (beta GalT), and the core 1 beta 3GalT-specific molecular chaperone, Cosmc, UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyl-transferase 2, were significantly decreased in tonsillar CD19-positive B lymphocytes from IgAN patients compared to control tonsillar tissues as determined by real-time RT-PCR. Tonsillar B cell beta 3GalT gene expression significantly correlated with estimated GFR and negatively correlated with proteinuria and histological injury score. Western blotting showed the protein expression of beta 3GalT in the tonsils to significantly decrease in IgAN in comparison to the controls. These data suggest the downregulation of beta 3GalT in tonsillar B lymphocytes to be closely associated with,the clinical characteristics of IgAN. (C) 2010 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.clim.2010.05.009

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  • Roles of Bone Morphogenetic Protein-6 in Aldosterone Regulation by Adrenocortical Cells

    Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Jiro Suzuki, Hirofumi Makino

    ACTA MEDICA OKAYAMA   64 ( 4 )   213 - 218   2010年8月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Aldosterone production occurs in the adrenal cortex, and is regulated primarily by angiotensin II (Ang II), potassium and adrenocorticotropin (ACTH). In the presence of the aldosterone stimulators, steroidogenesis is further governed by local autocrine and/or paracrine factors in the adrenal cortex. We reported the presence of functional bone morphogenetic protein (BMP) system in the adrenal cortex and also demonstrated that BMP-6 increases Ang II-induced aldosterone production, which could be involved in the "aldosterone breakthrough" phenomenon. Aldosterone breakthrough is the phenomenon by which circulating aldosterone concentrations increase above pre-treatment levels after longterm therapy with ACE inhibitors or Ang II type 1 receptor antagonists (ARB). This phenomenon may lead to important clinical consequences since increased aldosterone in a high-salt state facilitates cardiovascular and renal damage in hypertensive patients. We found that long-term ARB treatment reverses the reduction of aldosterone synthesis by adrenocortical cells, thereby causing "cellular aldosterone breakthrough". The availability of BMP-6 in the adrenal cortex may be at least partly involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

    DOI: 10.18926/AMO/40128

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  • Estrogen and glucocorticoid regulate osteoblast differentiation through the interaction of bone morphogenetic protein-2 and tumor necrosis factor-α in C2C12cells.

    Matsumoto Y, Otsuka F, Takano M, Mukai T, Yamanaka R, Takeda M, Miyoshi T, Inagaki K, Sada K, Makino H

    Molecular and Cellular Endocrinology   325 ( 1-2 )   118 - 127   2010年8月

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  • Functional relationship between fibroblast growth factor-8 and bone morphogenetic proteins in regulating steroidogenesis by rat granulosa cells

    Tomoko Miyoshi, Fumio Otsuka, Misuzu Yamashita, Kenichi Inagaki, Eri Nakamura, Naoko Tsukamoto, Masaya Takeda, Jiro Suzuki, Hirofumi Makino

    MOLECULAR AND CELLULAR ENDOCRINOLOGY   325 ( 1-2 )   84 - 92   2010年8月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Bone morphogenetic proteins (BMPs) have been recognized as crucial molecules in regulating ovarian physiology, with different BMPs having differential actions in FSH-induced estradiol production. To identify the roles of oocyte factors that modulate steroidogenesis controlled by BMPs, we here investigated the effects of FGF-8 in rat granulosa/oocyte co-cultures. FGF-8 potently suppressed FSH-induced estradiol production, but did not affect cAMP-induced estradiol produced by rat granulosa cells. FGF-8 had no effects on progesterone and cAMP production induced by FSH and forskolin. The inhibitory effects of FGF-8 on FSH-induced estradiol production were not altered by BMP-2, -4, -6 or -7. In the presence of FGF-8, BMPs suppressed FSH-induced progesterone by reducing cAMP, suggesting that FGF-8 and BMP independently regulate FSH receptor signaling. Notably, FGF-8-induced ERK and SAPK/JNK phosphorylation in granulosa cells, in which ERK activation was further enhanced by FSH and oocytes. Inhibition of ERK and SAPK/JNK reduced FSH-induced progesterone and cAMP levels, suggesting that the activation of these pathways enhances FSH-induced cAMP signaling. In addition, ERK inhibition upregulated FSH-induced estradiol synthesis, indicating that ERK pathway is also involved in suppressing aromatase activity in granulosa cells. Interestingly, FGF-8 enhanced BMP-induced Smad1/5/8 and Id-1-promoter activities with decreased expression of Smad6/7. Since the SAPK/JNK inhibitor inhibited FGF-8 effects in upregulating Id-1 transcription, SAPK/JNK appears to be involved in the mechanism by which FGF-8 enhances BMP-Smad signaling. Furthermore, in the presence of oocytes, the inhibition of endogenous FGF receptor signaling suppressed FSH- and forskolin-induced progesterone and cAMP, showing that endogenous FGF system is involved in activation of FSH-induced cAMP-PKA signaling via ERK and SAPK/JNK. Thus, the oocyte factor, FGF-8, not only suppresses FSH-induced estradiol production by activating ERK, but also enhances BMP-Smad signaling in granulosa cells. This interaction between FGF-8 and BMPs may play a key role in regulating steroidogenesis through oocyte-granulosa cell communication. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.mce.2010.04.012

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  • Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis.

    Kawabata T, Nishida K, Takasugi K, Ogawa H, Sada K, Kadota Y, Inagaki J, Hirohata S, Ninomiya Y, Makino H

    Arthritis Research and Therapy   12 ( 4 )   133 - 133   2010年7月

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  • Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling

    Misuzu Yamashita, Fumio Otsuka, Tomoyuki Mukai, Ryutaro Yamanaka, Hiroyuki Otani, Yoshinori Matsumoto, Eri Nakamura, Mariko Takano, Ken-ei Sada, Hirofumi Makino

    REGULATORY PEPTIDES   162 ( 1-3 )   99 - 108   2010年6月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    The mevalonate pathway plays a crucial role in bone metabolism. Here we examined roles of simvastatin in osteoclast function and differentiation induced by RANKL and BMP-2 using mouse macrophage-like MLC-6 cells and human osteoclast precursor cells. MLC-6 cells expressed BMP type-I and -II receptors and Smads as well as osteoclast markers including TRAP, RANK, cathepsin-K, M-CSF receptor, MMP-9 and calcitonin receptor. Treatment with RANKL and BMP-2 acted synergistically to stimulate RANK. TRAP and cathepsin-K expression in MLC-6 cells. Simvastatin suppressed osteoclastic activity shown by increases in RANK, TRAP and cathepsin-K expression induced by RANKL and BMP-2. In contrast simvastatin alone had no effects on the osteoclastic markers in MLC-6 cells. Simvastatin activated ERK. SAPK/JNK and AKT pathways and inactivated Ras in MLC-6 cells. Simvastatin had no effect on BMP-induced Smad1/5/8 phosphorylation regardless of RANKL stimulation. Since chemical inhibition of ERK, SAPK/JNK and AKT increased TRAP and cathepsin-K expression induced by BMP-2 and RANKL, these pathways are functionally involved in inhibition of osteoclastic activity. In addition, Src phosphorylation induced by RANKL, which is involved in osteoclast differentiation, was suppressed by simvastatin. We further confirmed an inhibitory mechanism of simvastatin on osteoclast differentiation using human osteoclast precursor cells which express BMP receptor and Smad signaling machinery. Simvastatin also activated ERK pathways and inactivated Src phosphorylation in human osteoclasts differentiated by M-CSF and RANKL treatments. The inhibition of TRAP and RANK expression by simvastatin was reversed by ERK inhibition, whereas Src inhibitor enhanced simvastatin-induced suppression of osteoclast markers. Collectively, our data show that simvastatin inhibits osteoclastic differentiation through inhibiting Src as well as enhancing MAPK/AKT pathways. (C) 2010 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.regpep.2010.03.003

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  • Optimal cut-off point of waist circumference for the diagnosis of metabolic syndrome in Japanese subjects

    Daisuke Ogawa, Kenji Kahara, Terunobu Shigematsu, Soichiro Fujii, Nobuhiko Hayakawa, Morihiro Okazaki, Hirofumi Makino

    JOURNAL OF DIABETES INVESTIGATION   1 ( 3 )   117 - 120   2010年6月

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    記述言語:英語   出版者・発行元:WILEY-BLACKWELL  

    Metabolic syndrome (MetS) has been redefined by a new criterion in Japan, in which waist circumference cut-off points, that is 85 cm for men and 90 cm for women, are used; however, objections are rising against this criterion. The present study examined the criterion for waist circumference to predict the accumulation of the components of MetS. In the present study, we used data for 5972 Japanese people who received annual health examinations, and 621 men (16.3%) and 51 women (2.4%) were diagnosed as having MetS. A cut-off point as a predictor for two or more components of MetS was evaluated by the sensitivity/specificity and a receiver operating characteristic analysis. The optimal point of waist circumference was estimated as being approximately 84 cm for men and 80 cm for women. We therefore recommend revising the cut-off value for the criterion of MetS in women according to our results and studies from other investigators. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00020.x, 2010)

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  • Relationship between Estimated Glomerular Filtration Rate (eGFR) and Metabolic Syndrome in Japanese

    Nobuyuki Miyatake, Kenichi Shikata, Hirofumi Makino, Takeyuki Numata

    ACTA MEDICA OKAYAMA   64 ( 3 )   203 - 208   2010年6月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We investigated the link between renal function as evaluated by estimated glomerular filtration rate (eGFR) and metabolic syndrome in Japanese. A total of 11,711 Japanese subjects, aged 20-79 years, were recruited in a cross-sectional clinical investigation. From this group, we further investigated the data on 1,576 subjects. eGFR was calculated using serum creatinine (Cr), age and sex. The diagnosis of metabolic syndrome was based on the Japanese criteria. In the first analysis, 288 men (7.8%) and 498 women (6.2%) were diagnosed with reduced eGFR (< 60 ml/min). eGFR was not correlated with anthropometric, body composition parameters in either sex. In the second analysis, in subjects without medications, 132 men (20.8%) and 15 women (1.6%) were diagnosed with metabolic syndrome. eGFR was lower in men with abdominal obesity and in women with hypertension was than in those without. Among Japanese not taking medications, lower eGFR may be a characteristic of men with abdominal obesity and of women with hypertension.

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  • Involvement of the bone morphogenetic protein system in endothelin- and aldosterone-induced cell proliferation of pulmonary arterial smooth muscle cells isolated from human patients with pulmonary arterial hypertension

    Ryutaro Yamanaka, Fumio Otsuka, Kazufumi Nakamura, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Yoshinori Matsumoto, Kengo F. Kusano, Hiroshi Ito, Hirofumi Makino

    HYPERTENSION RESEARCH   33 ( 5 )   435 - 445   2010年5月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Recent genetic studies have uncovered a link between familial and idiopathic pulmonary arterial hypertension (PAH) and germline mutations in the bone morphogenetic protein type-II receptor (BMPRII). The pathology of PAH is characterized by remodeling of the pulmonary arteries due to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Although increased endothelial injury and impaired suppression of PASMC proliferation are both critical for the cellular pathogenesis of PAH, a detailed molecular mechanism underlying PAH has yet to be elucidated. In the present study, we investigated the roles of the BMP system and other vasoactive factors associated with PAH (including endothelin (ET), angiotensin II (Ang II) and aldosterone) in the mitotic actions of PASMCs isolated from idiopathic and secondary PAH lungs. ET1 and aldosterone stimulated PASMC proliferation of idiopathic PAH more effectively than secondary PAH, whereas Ang II and ET3 failed to activate mitosis in either of the PASMC cell type. The effects of ET1 and aldosterone were blocked by bosentan, an ET type-A/B receptor (ETA/BR) antagonist, and eplerenone, a selective mineralocorticoid receptor (MR) blocker, respectively. Among the BMP ligands examined, BMP-2 and BMP-7, but not BMP-4 or BMP-6, significantly increased cell mitosis in both PASMC cell types. Notably, ET1- and aldosterone-induced mitosis and mitogen-activated protein kinase phosphorylation were significantly increased in the presence of BMP-2 and BMP-7 in PASMCs isolated from idiopathic PAH, although additive effects were not observed in PASMCs isolated from secondary PAH. Inhibition of extracellular signal-regulated kinase 1 (ERK1)/ERK2 signaling suppressed basal-, ET1- and aldosterone-induced PASMC mitosis more potently than that of stress-activated protein kinase/c-Jun NH2-terminal kinase inhibition. Given the fact that BMP-2 and BMP-7 upregulated ETA/BR and MR expression and that BMP-2 decreased 11 beta HSD2 (11 beta-hydroxysteroid dehydrogenase type 2) levels in PASMCs isolated from idiopathic PAH, BMPR-Smad signaling may have a key role in amplifying the ETA/BR and/or MR-ERK signaling in PASMCs of the PAH lung. Collectively, the functional link between BMP and ET and/or the MR system may be involved in the progress of PASMC mitosis, ultimately leading to the development of clinical PAH. Hypertension Research (2010) 33, 435-445; doi: 10.1038/hr.2010.16; published online 26 February 2010

    DOI: 10.1038/hr.2010.16

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  • Effects of icodextrin peritoneal dialysis solution on the peritoneal membrane in the STZ-induced diabetic rat model with partial nephrectomy

    Ai Nakao, Kazushi Nakao, Yuji Takatori, Syoichirou Kojo, Junko Inoue, Shigeru Akagi, Hitoshi Sugiyama, Jun Wada, Hirofumi Makino

    NEPHROLOGY DIALYSIS TRANSPLANTATION   25 ( 5 )   1479 - 1488   2010年5月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    Methods. Thirty-two male Wistar rats were divided into four groups: control Wistar rats with non-treated (n = 8), streptozotocin (STZ)-induced diabetic rats with 5/6 kidney ablation (n = 8), STZ-induced diabetic rats with 5/6 kidney ablation injected with a standard lactate-buffered 4.25% glucose-based PDF (Dianeal (R); n = 8) and STZ-induced diabetic rats with 5/6 kidney ablation injected with 7.5% icodextrin-based PDF (Extraneal (R); n = 8). Intraperitoneal injection was performed once daily with an instillation volume of 20 ml per injection during 8 weeks.
    Results. Chronic high-glucose-based PDF exposure resulted in increased vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expression, accumulation of advanced glycation end-products (AGEs), and up-regulation of the receptor for AGE (RAGE), which were ameliorated in the icodextrin-based PDF group. The peritoneal damages, such as neoangiogenesis and submesothelial fibrosis, were significantly reduced in icodextrin-based PDF compared to high-glucose-based PDF.
    Conclusions. Long-term in vivo exposure to high glucose-based PDF promotes the fibrosing process of peritoneal membranes. Icodextrin-based PDF may be helpful in slowing the PDF-induced deterioration of peritoneal function and prolonging the use of peritoneal dialysis in patients with diabetes.

    DOI: 10.1093/ndt/gfp479

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  • Microinflammation is a common risk factor for progression of nephropathy and atherosclerosis in Japanese patients with type 2 diabetes

    Nobuo Kajitani, Kenichi Shikata, Akihiko Nakamura, Tatsuaki Nakatou, Makoto Hiramatsu, Hirofumi Makino

    DIABETES RESEARCH AND CLINICAL PRACTICE   88 ( 2 )   171 - 176   2010年5月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Aim: This study aimed to evaluate the change of serum levels of proinflammatory molecules in patients with type 2 diabetes and clarify the involvement of these molecules in diabetic nephropathy and atherosclerosis.
    Methods: Sixty-six Japanese type 2 diabetic patients (T2DM) and 39 healthy control subjects were enrolled. We assessed clinical parameters, urinary albumin excretion rate (AER), brachial-ankle pulse wave velocity (baPWV), intima media thickness (IMT) and serum levels of proinflammatory molecules.
    Results: Serum levels of IL-6, IP-10 and MCP-1 were significantly higher in T2DM than in control subjects. In T2DM, serum levels of high-sensitivity (hs) CRP, IP-10, hsTNF-alpha, VCAM-1 and E-selectin were positively correlated with AER. Serum levels of IP-10, hsTNF-alpha and VCAM-1 were positively correlated with baPWV. Serum levels of hsCRP, IL-6, IP-10 and hSTNF-alpha were positively correlated with IMT. Multiple linear regression analysis revealed that serum levels of hsTNF-alpha were independently associated with AER (beta = 0.235, P = 0.038) and serum levels of IP-10 were independently associated with baPWV (beta = 0.209, P = 0.047) and IMT (beta = 0.303, P = 0.032).
    Conclusion: Our results suggest that low-grade inflammation, microinflammation, may be a common risk factor for diabetic nephropathy and atherosclerosis in Japanese type 2 diabetic patients. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

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  • Design and methods of a strategic outcome study for chronic kidney disease: Frontier of Renal Outcome Modifications in Japan

    Kunihiro Yamagata, Hirofumi Makino, Tadao Akizawa, Kunitoshi Iseki, Sadayoshi Itoh, Kenjiro Kimura, Daisuke Koya, Ichiei Narita, Tetsuya Mitarai, Masanobu Miyazaki, Yoshiharu Tsubakihara, Tsuyoshi Watanabe, Takashi Wada, Osamu Sakai

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   14 ( 2 )   144 - 151   2010年4月

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    記述言語:英語   出版者・発行元:SPRINGER  

    The continuous increase in the number of people requiring dialysis is a major clinical and socioeconomical issue in Japan and other countries. This study was designed to encourage chronic kidney disease (CKD) patients to consult a physician, enhance cooperation between nephrologists and general practices, and prevent the progression of kidney disease.
    Subjects comprise CKD patients aged between 40 and 74 years consulting a general physician, and patients in CKD stage 3 with proteinuria and diabetes or hypertension. This trial is a stratified open cluster-randomized study with two intervention groups: group A (weak intervention) and group B (strong intervention). We have recruited 49 local medical associations (clusters) in 15 different prefectures, which were classified into four regions (strata) based on the level of increase rate of dialysis patients. The patients in group A clusters were instructed initially to undergo treatment in accordance with the current CKD treatment guide, whereas patients in group B clusters were not only instructed in the same fashion but also received support from an information technology (IT)-based system designed to help achieve the goals of CKD treatment, consultation support centers, and consultations by dietitians visiting the local general practice offices. We assessed the rates of continued consultation, collaboration between general practitioners and nephrologists, and progression of CKD (as expressed by CKD stage).
    Through this study, filling the evidence-practice gap by facilitating effective communication and supporting general physicians and nephrologists, we will establish a CKD care system and decrease the number of advanced-stage CKD patients.

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  • Effects of Bone Morphogenetic Protein (BMP) on Adrenocorticotropin Production by Pituitary Corticotrope Cells: Involvement of Up-Regulation of BMP Receptor Signaling by Somatostatin Analogs

    Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Ryutaro Yamanaka, Kenichi Inagaki, Misuzu Yamashita, Hiroyuki Otani, Masaya Takeda, Jiro Suzuki, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

    ENDOCRINOLOGY   151 ( 3 )   1129 - 1141   2010年3月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    The mechanism by which somatostatin analogs suppress ACTH production by corticotropinomas has yet to be fully elucidated. We here studied the effects of somatostatin analogs on ACTH secretion using mouse corticotrope AtT20 cells focusing on the biological activity of bone morphogenetic proteins (BMPs). BMP ligands, receptors and Smads, and somatostatin receptors (SSTRs)-2, -3, and -5 were expressed in AtT20 cells. BMP-2, -4, -6, and -7 decreased basal ACTH production with BMP-4 effects being the most prominent. BMP-4 also inhibited CRH-induced ACTH production and proopiomelanocortin ( POMC) transcription. However, the decrease in CRH-induced cAMP accumulation caused by BMP-4 was not sufficient to completely account for BMP-4 actions, indicating that ACTH suppression by BMPs was not directly linked to cAMP inhibition. CRH-activated ERK1/ERK2, p38-MAPK, stress-activated protein kinase/c-Jun NH(2)-terminal kinase, protein kinase C, and Akt pathways and CRH-induced ACTH synthesis was significantly decreased in the presence of U0126 or SB203580. Because BMPs attenuated CRH-induced ERK and p38 phosphorylation, it was suggested that BMP-4 suppresses ACTH production by inhibiting CRH-induced ERK and p38 phosphorylation. Somatostatin analogs octreotide and pasireotide (SOM230) significantly suppressed CRH-induced ACTH and cAMP production in AtT20 cells and reduced ERK and p38 phosphorylation. Notably, CRH-induced ACTH production was enhanced in the presence of noggin, a BMP-binding protein. The inhibitory effects of octreotide and SOM230 on CRH-induced ACTH production were also attenuated by noggin, implying that the endogenous BMP system plays a key role in inhibiting CRH-induced ACTH production by AtT20 cells. The findings that OCT and SOM230 up-regulated BMP-Smad1/Smad5/Smad8 signaling and ALK-3 and BMPRII and down-regulated inhibitory Smad6/7 establish that the activation of endogenous BMP system is functionally involved in the mechanism by which somatostatin analogs suppress CRH-induced ACTH production. ( Endocrinology 151: 1129-1141, 2010)

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  • Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan): Rationale and study design

    Kenichi Shikata, Masakazu Haneda, Daisuke Koya, Yoshiki Suzuki, Yasuhiko Tomino, Kenichi Yamada, Shiro Maeda, Norito Kawakami, Takashi Uzu, Motonobu Nishimura, Chikage Sato, Daisuke Ogawa, Hirofumi Makino

    DIABETES RESEARCH AND CLINICAL PRACTICE   87 ( 2 )   228 - 232   2010年2月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    The prevalence of end-stage renal disease (ESRD) is uprising in the paralleled with the increase of chronic kidney disease (CKD) patients. Diabetic nephropathy (DN) is the most important underlying disease of CKD and a leading cause of ESRD in Japan. Intensified multifactorial intervention in patients with type 2 diabetes with microalbuminuria slows the progression to nephropathy, and progression of retinopathy and autonomic neuropathy. However, further studies are needed to establish the effect of intensified multifactorial treatment on DN with overt proteinuria. In this trial, doctors and co-medicals collaborate to treat the DN patients to prevent the deterioration of DN by multifactorial intensive therapy. Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) is an open, randomized controlled trial to evaluate the efficacy of renal protection of multifactorial intensive therapy in type 2 diabetes patients with overt proteinuria (urinary albumin-to-creatinine ratio >= 300 mg/g creatinine). The study has a targeted enrollment of 600 Japanese patients, and divided into two protocols by renal insufficiency (protocol A: serum creatinine: <1.2 mg/dl in male and <1.0 mg/dl in female, and protocol B: serum creatinine: 1.2-2.5 mg/dl in male and 1.0-2.5 mg/dl in female). The patients were allocated standard treatment or intensive multifactorial treatment. Intensive treatment was a step-wise implementation of behavior modification, pharmacological therapy targeting hyperglycaemia, hypertension, dyslipidaemia, and proteinuria. The primary outcome is the proteinuria in protocol A and the composite endpoint of time to the first occurrence of doubling of serum creatinine, ESRD (the need for chronic dialysis, or renal transplantation) or death in protocol B. The follow-up period is 5 years and the study ends in 2014. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

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  • Sensitization to alloxan-induced diabetes and pancreatic cell apoptosis in acatalasemic mice

    Yoko Kikumoto, Hitoshi Sugiyama, Tatsuyuki Inoue, Hiroshi Morinaga, Keiichi Takiue, Masashi Kitagawa, Naomi Fukuoka, Mizuho Saeki, Yohei Maeshima, Da-Hong Wang, Keiki Ogino, Noriyoshi Masuoka, Hirofumi Makino

    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE   1802 ( 2 )   240 - 246   2010年2月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    Human acatalasemia may be a risk factor for the development of diabetes mellitus. However, the mechanism by which diabetes is induced is still poorly understood. The impact of catalase deficiency on the onset of diabetes has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of diabetogenic alloxan. The incidence of diabetes was higher in acatalasemic mice treated with a high dose (180 mg/kg body weight) of alloxan. A higher dose of alloxan accelerated severe atrophy of pancreatic islets and induced pancreatic beta cell apoptosis in acatalasemic mice in comparison to wild-type mice. Catalase activity remained low in the acatalasemic pancreas without the significant compensatory up-regulation of glutathione peroxidase or superoxide dismutase. Furthermore, daily intraperitoneal injection of angiotensin II type 1 (AT1) receptor antagonist telmisartan (0.1 mg/kg body weight) prevented the development of alloxan-induced hyperglycemia in acatalasemic mice. This study suggests that catalase plays a crucial role in the defense against oxidative-stress-mediated pancreatic P cell death in an alloxan-induced diabetes mouse model. Treatment with telmisartan may prevent the onset of alloxan-induced diabetes even under acatalasemic conditions. (C) 2009 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.bbadis.2009.10.009

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  • Influencing Factors for Dietary Behaviors of Patients with Diabetic Nephropathy

    Kazuko Sumiyoshi, Chieko Kawata, Kenichi Shikata, Hirofumi Makino

    ACTA MEDICA OKAYAMA   64 ( 1 )   39 - 47   2010年2月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    The aim of this study was to clarify the factors influencing the dietary behavior of patients with diabetic nephropathy. One hundred twenty-two patients with type 2 diabetes were recruited from the outpatients of Okayama University Hospital in Okayama, Japan. We performed a cross-sectional study using a questionnaire including 206 items among 18 categories as follows: background factors, coping behavior (coping scale), degree of uncertainty in illness (uncertainty scale), and dietary behavior. The data were analyzed by correlation analysis, t-test, one-way analysis of variance, Pearson correlation analysis, and multiple regression analysis. We found that those patients with microalbuminuria alone tended to recognize more mild about their kidney status than those with macroalbuminuria and chronic renal failure. We also found that common factors influencing the dietary behavior of diabetic patients with and without nephropathy are as follows: 1. coping with the problem (beta = 03,12, P < 0.01); 2. anxiety about prognosis (beta = -0.344, p < 0.0 1); 3. sex (beta = -0.234, p < 0.05); 4. uncertainty regarding treatment (beta = 0.377, p < 0.01); 5. negative coping (beta = -0.354, p < 0.01); and 6. employment status (beta = 0.367, p < 0.01). Coping and uncertainty in illness had a significant relation to positive support and lack of support. To maintain appropriate dietary behavior in diabetic patients, medical staff need to determine what the social supports are important for the patient, and also to ensure good communication among healthcare personnel as well as positive support for patients and families.

    DOI: 10.18926/AMO/32856

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  • Fabry Disease Exhibiting Recurrent Stroke and Persistent Inflammation

    Yoko Kikumoto, Yasufumi Kai, Hiroshi Morinaga, Mutsunori Iga-Murahashi, Mikitaro Matsuyama, Takashi Sasaki, Hiroki Maruyama, Masaaki Shimotori, Hirofumi Makino, Hitoshi Sugiyama, Akihiko Okayama

    INTERNAL MEDICINE   49 ( 20 )   2247 - 2252   2010年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    We describe two cases of Fabry disease in non-blood-related Japanese men, manifesting recurrent stroke even after the start of enzyme replacement therapy. Both exhibited chronic inflammation and ocular involvement with elevated levels of serum C reactive protein prior to the onset of stroke. We, therefore, suggest the association among persistent inflammation, ocular involvement and recurrent stroke in a certain subset of Fabry disease patients. Both cases received enzyme replacement therapy with no improvement in inflammatory signs or laboratory data. These cases suggest that Fabry disease should be considered in young patients with cryptogenic stroke or CNS manifestations and fever of unknown origin.

    DOI: 10.2169/internalmedicine.49.3724

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  • Interaction of endothelin, aldosterone and bone morphogenetic proteins on mitotic actions of pulmonary arterial smooth muscle cells isolated from pulmonary arterial hypertension.

    Otsuka F, Yamanaka R, Nakamura K, Yamashita M, Takeda M, Suzuki J, Miyoshi T, Inagaki K, Makino H

    Endocrine Abstracts   21   123 - 123   2010年

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  • SLEの治療中に発見された両側副腎腫瘍によるCushing症候群の1例.

    大塚文男, 片山晶博, 塚本尚子, 山中龍太郎, 三好智子, 鈴木二郎, 武田昌也, 中村絵里, 稲垣兼一, 小倉俊郎, 槇野博史

    第21回間脳・下垂体・副腎系研究会報告   104 - 105   2010年

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  • Intergrowth between fibroblast factor-8 and bone morphogenetic proteins in regulation of ovarian steroidogenesis by rat granulose cells.

    Miyoshi T, Otsuka F, Yamashita M, Inagaki K, Suzuki J, Makino H

    Endocrine Abstracts   21   322 - 322   2010年

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  • Relation between the Estimated Glomerular Filtration Rate and Pulse Wave Velocity in Japanese

    Nobuyuki Miyatake, Kenichi Shikata, Hirofumi Makino, Takeyuki Numata

    INTERNAL MEDICINE   49 ( 14 )   1315 - 1320   2010年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Objective We investigated the link between renal function as evaluated by estimated glomerular filtration rate (eGFR) and pulse wave velocity (PWV) in Japanese without medications.
    Methods A total of 1,244 Japanese subjects, aged 20-79 years, were recruited in a cross-sectional clinical investigation study. They received no medications. eGFR was calculated using serum creatinine (Cr), age and sex. Peripheral arterial stiffness was evaluated by brachial-ankle PWV (baPWV).
    Results eGFR and baPWV were significantly correlated with age. eGFR was negatively correlated with baPWV (men: r=-0.308, p<0.0001, women: r=-0.293, p<0.0001). Twenty-six men (5.6%) and 35 women (4.5%) were diagnosed as reduced eGFR (eGFR <60 mL/min/1.73 m(2)). We compared clinical parameters between subjects with reduced eGFR (Group R) and without such reduction (Group N). baPWV in Group R was significantly higher than that in Group N even after adjusting for age. In women, systolic blood pressure in Group R was also significantly higher than that in Group N.
    Conclusion eGFR was closely associated with peripheral arterial stiffness in Japanese.

    DOI: 10.2169/internalmedicine.49.3085

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  • Overlap症候群(全身性エリテマトーデス、多発性筋炎)と診断した若年男性の1例.

    寺見隆宏, 小川大輔, 相田哲史, 槇野博史

    診断と治療   98 ( 5 )   863 - 865   2010年

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  • 糖尿病性腎症.

    槇野博史

    不安解消!糖尿病NHKきょうの健康   74 - 75   2010年

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  • CKDをめぐる最近の話題からーSLEと妊娠―.

    佐田憲映, 槇野博史

    腎と透析   69 ( 5 )   653 - 656   2010年

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  • まえがき―CENの育成に向けて.

    槇野博史

    日本腎臓学会誌   52 ( 1 )   28 - 29   2010年

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  • CKD地域医療連携への取組み.

    前島洋平, 槇野博史

    腎臓   32 ( 3 )   230 - 236   2010年

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  • CollectrinとACE2:その機能と異常.

    和田 淳, 安原章浩, 槇野博史

    Annual Review 腎臓   51 - 58   2010年

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  • CKD治療の基本方針

    村上和敏, 和田淳, 槇野博史

    Heart View   14 ( 3 )   335 - 341   2010年

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  • 慢性腎臓病(CKD)における抗血小板療法の実際特集:抗血小板薬・抗凝固薬のリスクとベネフィット.

    北川正史, 杉山 斉, 槇野博史

    診断と治療   98 ( 2 )   269 - 275   2010年

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  • 岡山市CKD-Network(OCKD-NET)とCKD地域医療連携.

    前島洋平, 槇野博史

    Pharma Medica   28 ( 2 )   65 - 68   2010年

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  • 特集にあたって.

    槇野博史

    Pharma Medica   28 ( 2 )   9 - 10   2010年

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  • 慢性腎臓病(CKD)CKD概念導入の背景と意義.

    井上達之, 槇野博史

    最新医学   65   9 - 18   2010年

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  • 糖尿病性腎症.

    槇野博史

    今日の診断指針   1057 - 1060   2010年

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  • 3.動脈硬化症の一次予防(EBMに基づく内科的治療)4)心腎関連の立場から.

    槇野博史, 北川正史

    日本内科学会雑誌   99 ( 3 )   27 - 33   2010年

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  • 脂質代謝異常と腎臓の接点 特集にあたって.

    槇野博史

    The Lipid   21 ( 2 )   114 - 115   2010年

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  • アミロイドーシス.

    木野村賢, 杉山 斉, 槇野博史

    病気と薬パーフェクトBOOK2010   61 ( 4 )   805 - 807   2010年

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  • 糖尿病とレニン・アンジオテンシン・アルドステロン(RAA)系.

    槇野博史, 前島洋平

    RAJ Journal   3   3 - 6   2010年

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  • チアゾリジン誘導体による腎保護効果.

    中司敦子, 和田 淳, 槇野博史

    The Lipid   21 ( 2 )   159 - 165   2010年

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  • 糖尿病性腎症.

    前島洋平, 槇野博史

    診断と治療   98 ( 4 )   601 - 605   2010年

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  • CKDの概念とその意味するところ特集:慢性腎臓病・一般臨床ではどのように対応していくか.

    北川正史, 杉山 斉, 槇野博史

    診断と治療   98 ( 4 )   554 - 559   2010年

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  • 高安病発見から1世紀―研究と診療のあゆみ 難治性血管炎研究の進歩.

    松本佳則, 佐田憲映, 槇野博史

    医学のあゆみ   233 ( 4 )   269 - 273   2010年

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  • CKD診療に関する一般内科医と腎臓専門医のギャップに関する調査結果.

    槇野博史

    セラピューティック・リサーチ   31 ( 4 )   585 - 595   2010年

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  • 慢性腎不全の診断,原因疾患および病態.

    高取優二, 中尾一志, 槇野博史

    総合臨床   59 ( 6 )   1354 - 1358   2010年

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  • インクレチンの膵外作用:腎臓.

    小寺 亮, 槇野博史

    医学の歩み   233 ( 5 )   385 - 389   2010年

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  • 特集SNARE複合体-膜融合の機構CollectrinとACE2:その機能と異常.

    和田 淳, 安原章浩, 槇野博史

    生体の科学   61 ( 3 )   263 - 268   2010年

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  • エビデンスに基づいた疾患別対応 二次性糸球体疾患の最大の原因・糖尿病性腎症治療における降圧薬の使い方.

    小川大輔, 槇野博史

    内科   106 ( 1 )   49 - 52   2010年

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  • CKDとは―心血管内分泌の立場から―.

    槇野博史

    CKDのサイエンス―基礎と臨床―   3 - 10   2010年

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  • オルメサルタンのアルブミン尿減少効果とその採用機序についての検討.

    村上和敏, 和田 淳, 槇野博史

    Theapeutic Research   31 ( 8 )   1149 - 1155   2010年

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  • Angiogenesis and chronic kidney disease.

    Maeshima Y, Makino H

    Fibrogenesis and Tissue Repair   3 ( 13 )   1 - 17   2010年

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  • 血管新生関連因子の遺伝子導入アプローチを用いた腹膜線維化進展機序の解明と新規治療法開発の基礎的検討.

    前島洋平, 田邉克幸, 杉山 斉, 槇野博史

    腎と透析   69   142 - 145   2010年

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  • 慢性合併症の臨床2(腎症)1.腎症の成因.

    四方賢一, 槇野博史

    糖尿病学の進歩2010   262 - 266   2010年

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  • 国立大学PDレジストリー腹膜透析2010.

    杉山 斉, 伊藤恭彦, 鶴屋和彦, 丸山弘樹, 後藤 眞, 中山昌明, 槇野博史, 松尾清一

    腎と透析   69   79 - 82   2010年

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  • 腹膜透析患者における腹膜機能廃絶重症化防止のための新たな腹膜機能検査の開発.

    喜多村真治, 杉山 斉, 平松 信, 槇野博史

    腎臓   33 ( 2 )   120 - 124   2010年

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  • Ⅱ.糖尿病性腎症 糖尿病性腎症の疾患概念と症候学.

    佐藤千景, 槇野博史

    糖尿病性細小血管症   68 ( 9 )   361 - 364   2010年

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  • CKD総論1.定義と概念AKIとCKDのすべて.

    菊本陽子, 杉山 斉, 槇野博史

    腎と透析   69   22 - 26   2010年

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  • Inflammatory Cytokine-induced Expression of Vasohibin-1 by Rheumatoid Synovial Fibroblasts

    Kohei Miyake, Keiichiro Nishida, Yasutaka Kadota, Hiroko Yamasaki, Tatsuyo Nasu, Daisuke Saitou, Katsuyuki Tanabe, Hikaru Sonoda, Yasufumi Sato, Yohei Maeshima, Hirofumi Makino

    ACTA MEDICA OKAYAMA   63 ( 6 )   349 - 358   2009年12月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Angriogenesis is an essential event in the development of synovial inflammation in rheumatoid arthritis (RA). The aim of the current study was to investigate the expression of vasohibin-1, a novel endothelium-derived vascular endothelial growth factor (VEGF)-inducible angiogenesis inhibitor, in the RA synovium, and to test the effect of inflammatory cytokines on the expression of vasohibin-1 by RA synovial fibroblasts (RASFs). Synovial tissue samples were obtained at surgery from patients with osteoarthritis (OA) and RA, and subjected to immunohistochemistry to investigate the expression and distribution of vasohibin-1 relevant to the degree of synovial inflammation. In an in vitro analysis, RASFs were used to examine the expression of vasohibin-1 and VEGF mRNA by real-time PCR after stimulation with VEGF or inflammatory cytokines under normoxic or hypoxic conditions. The immunohistochemical results showed that vasohibin-1 was expressed in synovial lining cells, endothelial cells, and synovial fibroblasts. In synovial tissue, there was a significant correlation between the expression of vasohibin-1 and histological inflammation score (p = 0.002, r = 0.842). In vitro, stimulation with VEGF induced the expression of vasohibin-1 mRNA in RASFs under normoxic conditions, and stimulation with cytokines induced vasohibin-1 mRNA expression under a hypoxic condition. These results suggest that vasohibin-1 was expressed in RA synovial tissue and might be regulated by inflammatory cytokines.

    DOI: 10.18926/AMO/31820

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  • Endothelial barrier protection by FTY720 under hyperglycemic condition: involvement of focal adhesion kinase, small GTPases, and adherens junction proteins

    Kei Sarai, Kenichi Shikata, Yasushi Shikata, Kazuyoshi Omori, Naomi Watanabe, Motofumi Sasaki, Shingo Nishishita, Jun Wada, Noriko Goda, Noriyuki Kataoka, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY   297 ( 4 )   C945 - C954   2009年10月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Sarai K, Shikata K, Shikata Y, Omori K, Watanabe N, Sasaki M, Nishishita S, Wada J, Goda N, Kataoka N, Makino H. Endothelial barrier protection by FTY720 under hyperglycemic condition: involvement of focal adhesion kinase, small GTPases, and adherens junction proteins. Am J Physiol Cell Physiol 297: C945-C954, 2009. First published August 5, 2009; doi:10.1152/ajpcell.00606.2008.-Recently, sphingosine 1-phosphate (S1P) has been highlighted as an endothelial barrier-stabilizing mediator. FTY720 is a S1P analog originally developed as a novel immunosuppressant. The phosphorylated form of FTY720 binds to S1P receptors to exert S1P-like biological effects, suggesting endothelial barrier promotion by FTY720. To elucidate whether FTY720 induces signaling events related to endothelial barrier enhancement under hyperglycemic conditions, human microvascular endothelial cells (HMVECs) preincubated with hyperglycemic (30 mM) medium were treated with 100 nM FTY720 for 3 h. Immunofluorescent microscopy and coprecipitation study revealed FTY720-induced focal adhesion kinase (FAK)-associated adherens junction (AJ) assembly at cell-cell contacts coincident with formation of a prominent cortical actin ring. FTY720 also induced transmonolayer electrical resistance (TER) augmentation in HMVEC monolayers in both normoglycemic and hyperglycemic conditions, implying endothelial barrier enhancement. Similar to S1P, site-specific FAK tyrosine phosphorylation analysis revealed FTY720-induced FAK [Y(576)] phosphorylation without phosphorylation of FAK [Y(397)/Y(925)]. Furthermore, FTY720 conditioned the phosphorylation profile of FAK [Y(397)/Y(576)/Y(925)] in hyperglycemic medium to the same pattern observed in normoglycemic medium. FTY720 challenge resulted in small GTPase Rac activation under hyperglycemic conditions, whereas increased Rho activity in hyperglycemic medium was restored to the basal level. Rac protein depletion by small interfering RNA (siRNA) technique completely abolished FTY720-induced FAK [Y(576)] phosphorylation. These findings strongly suggest the barrier protective effect of FTY720 on HMVEC monolayers in hyperglycemic medium via S1P signaling, further implying the possibility of FTY720 as a therapeutic agent of diabetic vascular disorder.

    DOI: 10.1152/ajpcell.00606.2008

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  • Clinical Usefulness of a Prognostic Score in Histological Analysis of Renal Biopsy in Patients with Lupus Nephritis

    Shoichiro Kojo, Ken-Ei Sada, Mizuho Kobayashi, Mie Maruyama, Yohei Maeshima, Hitoshi Sugiyama, Hirofumi Makino

    JOURNAL OF RHEUMATOLOGY   36 ( 10 )   2218 - 2223   2009年10月

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    記述言語:英語   出版者・発行元:J RHEUMATOL PUBL CO  

    Objective. To evaluate active and chronic lesions in association with renal outcome according to the International Society of Nephrology/Renal Pathology Society classification in patients with lupus nephritis.
    Methods. A retrospective analysis of 99 biopsy-proven subjects with lupus nephritis from 1990 to 2006 was performed in our center using the new classification. Each histological lesion was evaluated by multivariate survival analysis as predictive factor for renal insufficiency in patients with lupus nephritis, and independent predictors were graded to develop the prognostic score based on the regression coefficient. A receiver operating-characteristic curve based on the prognostic score was plotted to determine the most appropriate cutoff point.
    Results. In class IV, the IV-G group tended to exhibit a worse renal outcome compared with the IV-S group, but the difference was not significant (log-rank test, p = 0.4330). Independent histological predictors of poor renal outcome were extracapillary proliferation, glomerular sclerosis, and fibrous crescents analyzed by Cox proportional hazards model, while predictors of favorable renal outcome were hyaline thrombi and fibrous adhesions. By the prognostic score, renal outcome was significantly worse in the group with the higher score (>= 0.25) than in the group with the lower score (< 0.25) in class IV patients (log-rank test, p < 0.001).
    Conclusion. These results demonstrate the advantage of our prognostic score compared to subclasses in predicting the renal outcome of class IV patients [University Hospital Medical Information Network (UMIN) clinical trials registry, number UMIN 000001943]. (First Release Aug 1 2009; J Rheumatol 2009,36:2218-23; doi: 10.3899/jrheum.080793)

    DOI: 10.3899/jrheum.080793

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  • Historical chronology of basic and clinical research in diabetic nephropathy and contributions of Japanese scientists

    Jun Wada, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   13 ( 5 )   405 - 414   2009年10月

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    記述言語:英語   出版者・発行元:SPRINGER  

    The most problematic issue in clinical nephrology worldwide is the relentless and progressive increase in patients with end-stage renal disease (ESRD). Diabetic nephropathy has considerable impact on society in the areas of public health and social economy; many scientists are involved in research for the elucidation of the pathogenesis of diabetic nephropathy and for the prevention and cure of the disease. In contrast, diabetic nephropathy was a neglected or ignored disease in the historical era, and few dedicated physicians recognized the disease process of diabetic nephropathy. In this review, we look back on the history of basic and clinical research on diabetic nephropathy and survey the recent progress of the research, especially focusing on the contribution of Japanese scientists.

    DOI: 10.1007/s10157-009-0175-5

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  • Long-term effect of modification of dietary protein intake on the progression of diabetic nephropathy: a randomised controlled trial

    D. Koya, M. Haneda, S. Inomata, Y. Suzuki, D. Suzuki, H. Makino, K. Shikata, Y. Murakami, Y. Tomino, K. Yamada, S. I. Araki, A. Kashiwagi, R. Kikkawa

    DIABETOLOGIA   52 ( 10 )   2037 - 2045   2009年10月

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    記述言語:英語   出版者・発行元:SPRINGER  

    There is currently insufficient evidence to recommend a low-protein diet for type 2 diabetic patients with diabetic nephropathy. We assessed whether a low-protein diet could prevent the progression of diabetic nephropathy.
    This was a multi-site parallel randomised controlled trial for prevention of diabetic nephropathy progression among 112 Japanese type 2 diabetic patients with overt nephropathy. It was conducted in Japan from 1 December 1997 to 30 April 2006. The participants were randomly assigned using a central computer-generated schedule to either low-protein diet (0.8 g kg(-1) day(-1)) and normal-protein diet (1.2 g kg(-1) day(-1)), and were followed for 5 years. The participants and investigators were not blinded to the assignment. The primary outcomes were the annual change in estimated GFR and creatinine clearance, the incidence of doubling of serum creatinine and the time to doubling of baseline serum creatinine.
    The study was completed by 47 (84%) of 56 participants in the low-protein diet group and 41 (73%) of 56 participants in the normal-diet group. During the study period, the difference in mean annual change in estimated GFR between the low-protein diet and the normal-protein diet groups was -0.3 ml min(-1) 1.73 m(-2) (95% CI -3.9, 4.4; p = 0.93). The difference in mean annual change in creatinine clearance between the low-protein diet and the normal-protein diet groups was -0.006 ml s(-1) 1.73 m(-2) (95% CI -0.089, 0.112; p = 0.80). A doubling of serum creatinine was reached in 16 patients of the low-protein group (34.0%), compared with 15 in the normal-protein group (36.6%), the difference between groups being -2.6% (95% CI -22.6, 17.5; p = 0.80). The time to doubling of serum creatinine was similar in both groups (p = 0.66).
    It is extremely difficult to get patients to follow a long-term low-protein diet. Although in the low-protein group overall protein intake was slightly (but not significantly) lower, it did not confer renoprotection.
    Clinical trial registration: ClinicalTrials.gov NCT00448526
    Funding: Research grant from the Ministry of Health, Labour and Welfare of Japan.

    DOI: 10.1007/s00125-009-1467-8

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  • Regulation of GNRH production by estrogen and bone morphogenetic proteins in GT1-7 hypothalamic cells

    Hiroyuki Otani, Fumio Otsuka, Masaya Takeda, Tomoyuki Mukai, Tomohiro Terasaka, Tomoko Miyoshi, Kenichi Inagaki, Jiro Suzuki, Toshio Ogura, Mark A. Lawson, Hirofumi Makino

    JOURNAL OF ENDOCRINOLOGY   203 ( 1 )   87 - 97   2009年10月

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    記述言語:英語   出版者・発行元:BIOSCIENTIFICA LTD  

    Recent studies have shown that bone morphogenetic proteins (BMPs) are important regulators in the pituitary-gonadal endocrine axis. We here investigated the effects of BMPs on GNRH production controlled by estrogen using murine GT1-7 hypothalamic neuron cells. GT1-7 cells expressed estrogen receptor alpha (ER alpha; ESR1 as listed in MGI Database), ER beta (ESR2 as listed in MGI Database), BMP receptors, SMADs, and a binding protein follistatin. Treatment with BMP2 and BMP4 had no effect on Gnrh mRNA expression; however, BMP6 and BMP7 significantly increased Gnrh mRNA expression as well as GnRH production by GT1-7 cells. Notably, the reduction of Gnrh expression caused by estradiol (E(2)) was restored by cotreatment with BMP2 and BMP4, whereas it was not affected by BMP6 or BMP7. E(2) activated extracellular signal-regulated kinase (ERK) 1/2 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) signaling but did not activate p38-mitogen-activated protein kinase (MAPK) signaling in GT1-7 cells. Inhibition of ERK1/ERK2 reversed the inhibitory effect of estrogen on Gnrh expression, whereas SAPK/JNK inhibition did not affect the E(2) actions. Expression levels of Era and Er beta were reduced by BMP2 and BMP4, but were increased by BMP6 and BMP7. Treatment with an ER antagonist inhibited the E, effects on Gnrh suppression including reduction of E(2)-induced ERK phosphorylation, suggesting the involvement of genomic ER actions in Gnrh suppression. BMP2 and BMP4 also suppressed estrogen-induced phosphorylation of ERK1/ERK2 and SAPK/JNK signaling, suggesting that BMP2 and BMP4 downregulate estrogen effects by attenuating ER-MAPK. signaling. Considering that BMP6 and BMP7 increased the expression of alpha 1E-subunit of R-type calcium channel (Cacna1e), which is critical for GNRH secretion, it is possible that BMP6 and BMP7 directly stimulate GNRH release by GT1-7 cells. Collectively, a newly uncovered interaction of BMPs and ER may be involved in controlling hypothalamic GNRH production and secretion via an autocrine/paracrine mechanism. Journal of Endocrinology (2009) 203, 87-97

    DOI: 10.1677/JOE-09-0065

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  • Vasohibin-1, a Negative Feedback Regulator of Angiogenesis, Ameliorates Renal Alterations in a Mouse Model of Diabetic Nephropathy

    Tatsuyo Nasu, Yohei Maeshima, Masaru Kinomura, Kumiko Hirokoshi-Kawahara, Katsuyuki Tanabe, Hitoshi Sugiyama, Hikaru Sonoda, Yasufumi Sato, Hirofumi Makino

    DIABETES   58 ( 10 )   2365 - 2375   2009年10月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    OBJECTIVE-The involvement of proangiogenic factors such as vascular endothelial growth factor as well as the therapeutic efficacy of angiogenesis inhibitors in early diabetic nephropathy has been reported. Vasohibin-1 (VASH-1) is a unique endogenous angiogenesis inhibitor that is induced in endothelial cells by proangiogenic factors. We investigated the therapeutic efficacy of VASH-1 in an early diabetic nephropathy model.
    RESEARCH DESIGN AND METHODS-Streptozotocin-induced type 1 diabetic mice received intravenous injections of adenoviral vectors encoding VASH-1 (AdhVASH-1) or beta-gal (AdLacZ) every other week and were killed after 28 days.
    RESULTS-Treatment with AdhVASH-1 resulted in sustained increase in the protein levels of VASH-1 in the liver and sera, in the absence of any inflammatory alterations. AdhVASH-1 treatment significantly suppressed renal hypertrophy, glomerular hypertrophy, glomerular hyperfiltration, albuminuria, increase of the CD31(+) glomerular endothelial area, F4/80(+) monocyte/macrophage infiltration, the accumulation of type IV collagen, and mesangial matrix compared with AdLacZ-treated diabetic mice. Increase in the renal levels of transforming growth factor-beta 1, monocyte chemoattractant protein-1, and receptor for advanced glycation end products in diabetic animals was significantly suppressed by AdhVASH-1 (real-time PCR and immunoblot). VASH-1 significantly suppressed the increase of transforming growth factor-beta, monocyte chemoattractant protein-1, and receptor for advanced glycation end products, induced by high ambient glucose in cultured mouse mesangial cells. Increased phosphorylation of VEGFR2 was suppressed in AdVASH-1-treated diabetic animals and in cultured glomerular endothelial cells. Endogenous mouse VASH-1 was localized to the mesangial and endothelial area in glomeruli of diabetic mice.
    CONCLUSIONS-These results suggest the potential therapeutic efficacy of VASH-1 in treating early diabetic nephropathy potentially mediated via glomerular endothelial and mesangial cells. Diabetes 58:2365-2375, 2009

    DOI: 10.2337/db08-1790

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  • A case of immunotactoid glomerulopathy exhibiting nephrotic syndrome successfully treated with corticosteroids and antihypertensive therapy

    Masaru Kinomura, Yohei Maeshima, Ryo Kodera, Hiroshi Morinaga, Daisuke Saito, Kazushi Nakao, Hiroyuki Yanai, Kenei Sada, Hitoshi Sugiyama, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   13 ( 4 )   378 - 384   2009年8月

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    記述言語:英語   出版者・発行元:SPRINGER  

    We report a case of immunotactoid glomerulopathy (ITG) with cerebral hemorrhage and hypocomplementemia, with successful therapeutic outcome following the corticosteroids and antihypertensive treatment. A 70-year-old man presented with facial edema in October 2006. One day prior to his referral, he experienced speech disturbance, headache, and vomiting, and on the next day he was referred to our hospital. The laboratory examination revealed massive proteinuria (11.3 g/day) and hematuria. The total serum hemolytic complement (CH50) was decreased to 23 U/ml and C4 component was decreased to 7.5 mg/dl, whereas C3 component remained within normal limits (82 mg/dl). Brain computed tomography scan showed high-density lesions in the left parieto-occipital area suggesting subcortical cerebral hemorrhage. Renal biopsy revealed diffuse subendothelial PAS-positive depositions. Immunofluorescence studies revealed intensive deposition of IgG, IgA, C3, C1q, Fibrinogen, and kappa light chain with granular pattern in the capillary and mesangial area. Electron microscopic examination revealed regularly arranged microtubular deposits, appearing as 21-33 nm in diameter. Based on these findings, this patient was diagnosed as ITG complicated with cerebral hemorrhage and hypocomplementemia. He received oral prednisolone (30 mg/day), resulting in reduction of proteinuria, improvement of hypocomplementemia, and prevention of renal functional deterioration. This case demonstrates that accurate diagnosis of ITG may result in successful therapeutic outcome.

    DOI: 10.1007/s10157-009-0166-6

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  • Enhanced interaction between focal adhesion and adherens junction proteins: Involvement in sphingosine 1-phosphate-induced endothelial barrier enhancement

    Xiaoguang Sun, Yasushi Shikata, Lichun Wang, Kazuyoshi Ohmori, Naoko Watanabe, Jun Wada, Kenichi Shikata, Konstantin G. Birukov, Hirofumi Makino, Jeffrey R. Jacobson, Steven M. Dudek, Joe G. N. Garcia

    MICROVASCULAR RESEARCH   77 ( 3 )   304 - 313   2009年5月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Sphingosine 1-phosphate (S1P) is an important vascular barrier regulatory agonist which enhances the junctional integrity of human lung endothelial cell monolayers. We have now demonstrated that S1P induced cortical actin ring formation and redistribution of focal adhesion kinase (FAK) and paxillin to the cell periphery suggesting the critical role of cell-cell adhesion in endothelial barrier enhancement. Co-immunoprecipitation studies revealed increased association of VE-cadherin with FAK and paxillin in S1P-challenged human pulmonary artery endothelial cell (HPAEC) monolayers. Furthermore, SIP-induced enhancement of VE-cadherin interaction with alpha-catenin and beta-catenin was associated with the increased formation of FAK-beta-catenin protein complexes. Depletion of beta-catenin (siRNA) resulted in loss of S1P-mediated VE-cadherin association with FAK and paxillin rearrangement. Furthermore, transendothelial electrical resistance (an index of barrier function) demonstrated that beta-catenin siRNA significantly attenuated S1P-induced barrier enhancement. These results demonstrate a mechanism of S1P-induced endothelial barrier enhancement via beta-catenin-linked adherens junction and focal adhesion interaction. (C) 2009 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.mvr.2008.12.004

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  • p38-Mitogen-Activated Protein Kinase Stimulated Steroidogenesis in Granulosa Cell-Oocyte Cocultures: Role of Bone Morphogenetic Proteins 2 and 4

    Kenichi Inagaki, Fumio Otsuka, Tomoko Miyoshi, Misuzu Yamashita, Mina Takahashi, Junko Goto, Jiro Suzuki, Hirofumi Makino

    ENDOCRINOLOGY   150 ( 4 )   1921 - 1930   2009年4月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    Roles of the p38-MAPK pathway in steroidogenesis were investigated using coculture of rat granulosa cells with oocytes. Activin and FSH readily phosphorylated p38 in granulosa cells. Activin effect on p38 phosphorylation was abolished by a selective activin receptor-like kinase-4, -5, and -7 inhibitor, SB431542. SB431542 decreased FSH-induced estradiol but had no effect on progesterone production with a marginal cAMP reduction, suggesting that endogenous activin is primarily involved in estradiol synthesis. FSH-induced p38 activation was not affected either by SB431542 or follistatin, suggesting that FSH activates p38 not through the endogenous activin. Bone morphogenetic protein (BMP)-2 and BMP-4 also enhanced FSH-induced p38 phosphorylation, which was augmented by oocyte action. A specific p38 inhibitor, SB203580, decreased FSH-induced estradiol production. However, FSH-induced cAMP accumulation was not changed by SB203580, suggesting that p38 activation is linked to estradiol synthesis independently of cAMP. BMP-2 and BMP-4 inhibited FSH- and forskolin (FSK)-induced progesterone and cAMP synthesis regardless of oocyte action. BMP-2, BMP-4, and activin increased FSH- induced estradiol production, which was enhanced in the presence of oocytes. In contrast to activin that enhanced FSK-induced estradiol, BMP-2 and BMP-4 had no effects on FSK-induced estradiol production, suggesting that BMP-2 and BMP-4 directly activate FSH- receptor signaling. Given that activin increased, but BMP-2 and BMP-4 decreased, FSH- induced cAMP, the effects of BMP-2 and BMP-4 on estradiol enhancement appeared to be diverged from the cAMP-protein kinase A pathway. Thus, BMP-2 and BMP-4 differentially regulate steroidogenesis by stimulating FSH- induced p38 and suppressing cAMP. The former is involved in estradiol production and enhanced by oocyte action, whereas the latter leads to reduction of progesterone synthesis. (Endocrinology 150: 1921-1930, 2009)

    DOI: 10.1210/en.2008-0851

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  • Enhancement of aldosterone-induced catecholamine production by bone morphogenetic protein-4 through activating Rho and SAPK/JNK pathway in adrenomedullar cells

    Junko Goto, Fumio Otsuka, Misuzu Yamashita, Jiro Suzuki, Hiroyuki Otani, Hiroko Takahashi, Tomoko Miyoshi, Yukari Mimura, Toshio Ogura, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM   296 ( 4 )   E904 - E916   2009年4月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Goto J, Otsuka F, Yamashita M, Suzuki J, Otani H, Takahashi H, Miyoshi T, Mimura Y, Ogura T, Makino H. Enhancement of aldosterone-induced catecholamine production by bone morphogenetic protein-4 through activating Rho and SAPK/JNK pathway in adrenomedullar cells. Am J Physiol Endocrinol Metab 296: E904-E916, 2009. First published February 9, 2009; doi:10.1152/ajpendo.90840.2008.-Here we investigated the effects of mineralocorticoid in the regulation of catecholamine biosynthesis using rat pheochromocytoma PC12 cells. Expression of mineralocorticoid receptor (MR) was confirmed in undifferentiated PC12 cells. Aldosterone stimulated dopamine production by PC12 cells without any increase in cAMP activity. Aldosterone-induced dopamine accumulation was enhanced in accordance with the increase in the rate-limiting enzyme tyrosine hydroxylase (TH). Blocking MR with eplerenone suppressed aldosterone-induced increases of TH mRNA and dopamine production. A glucocorticoid receptor (GR) antagonist, RU-486, attenuated dexamethasone-but not aldosterone-induced TH expression. Cycloheximide reduced both aldosterone-and dexamethasone-induced TH mRNA. A SAPK/JNK inhibitor, SP600125, suppressed aldosterone-induced TH mRNA expression; however, the aldosterone-induced TH expression was not affected by inhibition of ERK1/2, p38-MAPK, Rho-kinase, PI 3-kinase, and PKC. It was of note that cotreatment with eplerenone and SP600125 restored aldosterone-induced TH mRNA expression to basal levels. To investigate the involvement of bone morphogenetic protein (BMP) actions in aldosterone-induced catecholamine production, we examined the effects of BMP-4 and BMP-7, which are expressed in the adrenal medulla, on catecholamine biosynthesis. BMP-4 preferentially enhanced aldosterone-induced TH mRNA and dopamine production, although BMP-4 alone did not affect TH expression. The BMP-4 enhancement of aldosterone-induced TH expression was not observed in cells treated with eplerenone. BMP-4 did not affect MR expression of PC12 cells; however, it did enhance aldosterone-induced SAPK/JNK phosphorylation. Inhibition of SAPK/JNK or Rho suppressed BMP-4 enhancement of aldosterone-induced TH expression. Collectively, our findings demonstrate that aldosterone stimulates catecholamine biosynthesis in adrenomedullar cells via MR through genomic action and partly through nongenomic action by Rho-SAPK/JNK signaling, the latter of which is facilitated by BMP-4. A functional link between MR actions and endogenous BMP may be involved in the catecholamine production.

    DOI: 10.1152/ajpendo.90840.2008

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  • Effects of Growth Hormone Reduction in a Patient with Polycystic Ovary Syndrome Complicated with Acromegaly

    Junko Goto, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Jiro Suzuki, Tomoko Miyoshi, Toshio Ogura, Yasuhiko Kamada, Hirofumi Makino

    ENDOCRINE JOURNAL   56 ( 1 )   157 - 160   2009年2月

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    記述言語:英語   出版者・発行元:JAPAN ENDOCRINE SOC  

    We report a rare case of polycystic ovary syndrome (PCOS) complicated with acromegaly due to a growth hormone (GH)-producing pituitary adenoma. Complete removal of the pituitary adenoma Successfully reduced circulating levels of GH and insulin-like growth factor (IGF)-1, which, in turn, resulted in the amelioration of gonadal dysfunction, hyperandrogenism, lutenizing hormone hypersecretion, and severe insulin resistance. This clinical complication suggests that activation of systemic GH-IGF-1 axis is potentially involved in the development of PCOS.

    DOI: 10.1507/endocrj.K08E-215

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  • Olmesartan and Temocapril Prevented the Development of Hyperglycemia and the Deterioration of Pancreatic Islet Morphology in Otsuka-Long-Evans-Tokushima Fatty Rats

    Masanobu Kaihara, Yoshio Nakamura, Taro Sugimoto, Haruhito A. Uchida, Hisanao Norii, Yoshihisa Hanayama, Hirofumi Makino

    ACTA MEDICA OKAYAMA   63 ( 1 )   35 - 42   2009年2月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We investigated the impact of olmesartan and temocapril on pancreatic islet beta-cells during the development of diabetes mellitus using Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats. Four-week-old male OLETF rats were fed standard chow (untreated: n = 5), or chow containing either 0.005% olmesartan (n = 5) or 0.01% temocapril (n = 5) until being sacrificed at 35 weeks of age. Pancreas sections were double-stained with anti-insulin and anti-glucagon antibodies. The percent areas of beta-cells, alpha-cells and non-alpha-non-beta-cells were compared among groups. In untreated OLETF rats, the fasting plasma glucose (FPG) level was elevated at the 18th week and remained elevated until the 35th week. On the other hand, no significant elevation in FPG levels was observed in otmesartan- or temocapril-treated rats. Pancreatic islets from olmesartan-treated rats were significantly smaller in size as compared with those from untreated OLETF rats. Furthermore, the average area occupied by beta-cells as a fraction of the total area of an individual islet was significantly higher in olmesartan- or temocapril-treated rats than that in untreated OLETF rats. Olmesartan and temocapril both prevented the development of hyperglycemia, possibly through the prevention of islet beta-cell loss in spontaneously diabetic OLETF rats.

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  • Urinary excretions of lipocalin-type prostaglandin D synthase predict renal injury in type-2 diabetes: a cross-sectional and prospective multicentre study

    Yoshio Uehara, Hirofumi Makino, Kousuke Seiki, Yoshihiro Urade

    NEPHROLOGY DIALYSIS TRANSPLANTATION   24 ( 2 )   475 - 482   2009年2月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    Backgrounds. Urinary excretions of lipocalin-type prostaglandin D synthase/beta-trace (L-PGDS) probably reflect the increased permeability of injured glomerular capillary walls of the kidney. We tested the hypothesis in cross-sectional and prospective studies that urinary L-PGDS excretions predict renal injury in type-2 diabetes.
    Methods. (1) In the cross-sectional studies, we evaluated whether urinary L-PGDS excretions were able to predict renal diseases in a pooled population including 793 healthy subjects and 200 patients with various forms of renal diseases. (2) We determined the cut-off point of urinary L-PGDS excretions to predict >= 30 mg/gCr albuminuria in 666 patients with type-2 diabetes. (3) In the prospective study, 121 type-2 diabetic patients with < 30 mg/gCr albuminuria were followed for almost 2 years to examine whether urinary L-PGDS excretions predict the future status of renal injury in type-2 diabetes.
    Results. (1) In the cross-sectional studies, receiver operating characteristic analysis revealed that urinary L-PGDS excretions better predicted the patients with kidney diseases than the other markers of renal injury. (2) It was also demonstrated that >= 4.2 mg/gCr urinary L-PGDS excretions better predicted >= 30 mg/gCr albuminuria in type-2 diabetic patients than other markers. (3) The prospective study revealed that in type-2 diabetic patients with < 30 mg/ gCr albuminuria, the patients with >= 4.2 mg/gCr urinary L-PGDS excretions more likely exhibited the renal injury during the follow-up periods than those with < 4.2 mg/gCr urinary L-PGDS excretions.
    Conclusions. Urinary L-PGDS excretions reflect the current increased permeability of injured glomerular capillary walls and better predict the future status of renal injury in type-2 diabetes with < 30 mg/gCr albuminuria.

    DOI: 10.1093/ndt/gfn515

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  • Effects of Growth Hormone Reduction in a Patient with Polycystic Ovary Syndrome Complicated with Acromegaly

    Junko Goto, Fumio Otsuka, Kenichi Inagaki, Naoko Tsukamoto, Jiro Suzuki, Tomoko Miyoshi, Toshio Ogura, Yasuhiko Kamada, Hirofumi Makino

    ENDOCRINE JOURNAL   56 ( 1 )   157 - 160   2009年2月

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    記述言語:英語   出版者・発行元:JAPAN ENDOCRINE SOC  

    We report a rare case of polycystic ovary syndrome (PCOS) complicated with acromegaly due to a growth hormone (GH)-producing pituitary adenoma. Complete removal of the pituitary adenoma Successfully reduced circulating levels of GH and insulin-like growth factor (IGF)-1, which, in turn, resulted in the amelioration of gonadal dysfunction, hyperandrogenism, lutenizing hormone hypersecretion, and severe insulin resistance. This clinical complication suggests that activation of systemic GH-IGF-1 axis is potentially involved in the development of PCOS.

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  • Adrenal ganglioneuroma accompanying catecholamine-producing adrenocortical cells

    J. Goto, F. Otsuka, M. Omori, H. Makino

    JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION   32 ( 2 )   192 - 192   2009年2月

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:EDITRICE KURTIS S R L  

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  • Usefulness of ISN/RPS Classification of Lupus Nephritis

    Ken-Ei Sada, Hirofumi Makino

    JOURNAL OF KOREAN MEDICAL SCIENCE   24   S7 - S10   2009年1月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:KOREAN ACAD MEDICAL SCIENCES  

    About 50-80% of patients with lupus suffer from lupus nephritis which is one of major causes of morbidity and mortality. Renal pathologists and nephrologists should evaluate the degree of histological damages to establish therapeutic plans for lupus nephritis. In order to standardize definitions, to emphasize clinically relevant lesions, and to improve interobserver reproducibility, the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed. Recently, several retrospective validation studies concerning the utility of the ISN/RPS classification, especially among class IV, were performed. In these reports, reproducibility is improved by the definition of diagnostic term, but the outcome related with classification, especially in class IV, is controversial. We performed retrospective analysis of 99 biopsy-proven subjects with lupus nephritis in our facility using the ISN/RPS classification. The class IV-G group tended to exhibit a worse renal outcome, but the difference compared with IV-S was not significant. In a Cox proportional hazards models, Independent histological predictors of poor renal outcome were extracapillary proliferation, glomerular sclerosis and fibrous crescents, while hyaline thrombi and fibrous adhesions were of favorable renal outcome. Both were similarly observed in IV-G and IV-S. The more qualitative categorization by the response to standard treatment may be needed to emphasize clinically relevant lesion related to renal Outcome.

    DOI: 10.3346/jkms.2009.24.S1.S7

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  • エビデンスに基づくCKD診療ガイドライン2009.

    前島洋平, 槇野博史

    日本腎臓学会編   1 - 283   2009年

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  • Bone morphogenetic protein-2 and-4enhance FSH-induction through oocyte-granulosa cell interaction.

    Miyoshi T, Otsuka F, Inagaki J, Yamashita M, Goto J, Tsukamoto N, Takeda M, Suzuki J, Makino H

    Endocrine Abstracts   19   OC38-OC38   2009年

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  • 低Na血症を契機に発見された結核性リンパ節炎の1例.

    大谷寛之, 大塚文男, 塚本尚子, 中村絵里, 後藤順子, 三好智子, 武田昌也, 鈴木二郎, 三村由香里, 小倉俊郎, 槇野博史

    日本内分泌学会雑誌 第19回臨床内分泌代謝UpdateProceeding   85   54 - 55   2009年

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  • Inhibitory effects of bone morphogenetic proteins on estorogen-induced proliferation of breast cancer cells.

    Otsuka F, Takahashi M, Yamashita M, Otani H, Goto J, Ogura T, Doihara H, Makino H

    Endocrine Abstracts   19   164 - 164   2009年

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  • beta-Blocker Prescription and Outcomes in Hemodialysis Patients from The Japan Dialysis Outcomes and Practice Patterns Study

    Kazushi Nakao, Hirofumi Makino, Satoshi Morita, Yoshimitsu Takahashi, Tadao Akizawa, Akira Saito, Yasushi Asano, Kiyoshi Kurokawa, Shunichi Fukuhara, Takashi Akiba

    NEPHRON CLINICAL PRACTICE   113 ( 3 )   C132 - C139   2009年

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    記述言語:英語   出版者・発行元:KARGER  

    Background/Aims: Given the clear benefits of mortality reduction observed for most beta-blockers in clinical trials, they are relatively underused in hemodialysis patients. Since the outcomes associated with the use of beta-blockers are not fully known, we investigated their effect on mortality among a cohort of hemodialysis patients. Methods: Data were analyzed from the Dialysis Outcomes and Practice Patterns Study phase II for 2,286 randomly selected patients on hemodialysis in Japan. Treatment with beta-blockers was the major predictor variable. The main outcome measure was all-cause mortality. Cox regression analysis was used to assess an association between treatment with beta-blockers and the risk of death. Results: 247 patients (11.9%) were administered beta-blockers and 1,828 patients (88.1%) were not. Whereas patients treated with beta-blockers had a higher prevalence of hypertension and coronary heart disease, Kaplan-Meier analysis revealed that all-cause mortality rates were significantly (p < 0.007) decreased in patients treated with beta-blockers compared to those without. In multivariable, fully adjusted models, treatment with beta-blockers was also independently associated with reduced all-cause mortality (hazard ratio = 0.48; p = 0.02). Conclusion: This study indicated a possible association between the use of beta-blockers and reduced risk of mortality in hemodialysis patients. These results should be confirmed in further randomized controlled trials. Copyright (C) 2009 S. Karger AG, Basel

    DOI: 10.1159/000232593

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  • 全身性疾患による腎障害 2.膠原病および近縁疾患による障害.

    佐田憲映, 槇野博史

    新臨床内科学第9版   1027 - 1031   2009年

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  • INNOVATION.

    小川大輔, 槇野博史

    血圧   16 ( 1 )   32 - 35   2009年

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  • CKDの管理・診療連携のポイント.

    槇野博史

    Medi.magazine   1   4 - 9   2009年

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  • 慢性腎臓病編 早期治療で心血管疾患を防ぐ.

    槇野博史

    日本経済新聞   36 - 36   2009年

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  • ループス腎炎に対する抗CD20モノクローナル抗体(リツキシマブ)の効果.

    佐田憲映, 槇野博史

    AnnualReview腎臓2009   258 - 261   2009年

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  • 6.尿検査蛋白.

    小林みずほ, 杉山 斉, 槇野博史

    臨床検査ガイド2009~2010 これだけは必要な検査のすすめかた・よみかた   946 - 948   2009年

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  • 糖尿病と異所性石灰化.

    古城昭一郎, 中尾一志, 槇野博史

    腎と透析   66 ( 2 )   198 - 201   2009年

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  • 健康チェックQ&A 8人に1人が!?新たな国民病慢性腎臓病(CKD).

    槇野博史

    月刊みすみ   ( 510 )   3 - 3   2009年

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  • 糖尿病性腎症の現状と今後―オーバービュー.

    小川大輔, 槇野博史

    Nephrology Frontier   8 ( 1 )   23 - 25   2009年

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  • 糖尿病の療養指導Q&A.

    小川大輔, 槇野博史

    PRACTICE   26 ( 2 )   197 - 199   2009年

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  • 新しいリスクファクターとしてのCKD.

    槇野博史

    日本経済新聞   28 - 28   2009年

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  • 平成20年度日本腎臓財団褒賞受賞者を囲んで.

    槇野博史

    腎臓   31 ( 3 )   248 - 271   2009年

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  • 透析導入や心血管疾患の増加を防ぐため新しい疾患概念で国民にアピール~定期的な検尿や腎機能評価の必要性を強調~.

    槇野博史

    MEDICAMENT NEWS   ( 1973 )   1 - 3   2009年

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  • 話題 INNOVATION試験.

    小川大輔, 槇野博史

    内分泌・糖尿病科   28 ( 4 )   333 - 336   2009年

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  • 糖尿病性腎症 CKD患者における診断・評価の要点.

    前島洋平, 槇野博史

    腎と透析   67   227 - 230   2009年

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  • 血液透析; 透析患者の血糖管理.

    高取優二, 中尾一志, 槇野博史

    腎不全ハンドブック‐CKDから先端透析療法:uptodate   170 - 171   2009年

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  • テルミサルタン.

    小川大輔, 槇野博史

    診断と治療   97 ( 4 )   812 - 816   2009年

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  • 特集 腎疾患―最近の進展慢性腎臓病とは.

    井上達之, 杉山 斉, 槇野博史

    Cefiro 特集 腎疾患―最近の進展―   9   5 - 9   2009年

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  • 維持輸液、経腸栄養のインスリン使用の実際.

    佐藤千景, 四方賢一, 槇野博史

    総合臨床「今すぐに役立つ輸液ガイドブック」   58   1032 - 1038   2009年

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  • 糖尿病性腎症の理解と予防.

    梶谷展生, 宮本 聡, 小寺 亮, 四方賢一, 槇野博史

    外来看護最前線 生活習慣病&外来がん看護   14 ( 4 )   32 - 43   2009年

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  • 糖尿病性腎症による透析患者の減少は可能か?.

    槇野博史

    最新医学・別冊新しい診断と治療のABC61   153 - 159   2009年

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  • 糖尿病性腎症 第4章 管理・治療 病診連携.

    前島洋平, 槇野博史

    最新医学・別冊新しい診断と治療のABC61   138 - 144   2009年

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  • 特集 知っておきたい透析の知識とケアの極意 腎臓病の考え方;CKDについて.

    古城昭一郎, 中尾一志, 槇野博史

    臨床看護   35 ( 6 )   832 - 838   2009年

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  • 糖尿病が引き起こす細小血管症 ③糖尿病性腎症.

    小寺 亮, 四方賢一, 槇野博史

    からだの科学   ( 261 )   88 - 93   2009年

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  • PREVEND IT Prevention of Renal and Vascular Endstage Disease Intervention Trial.

    田邉克幸, 前島洋平, 槇野博史

    DATA UPDATE 循環系 第4版   344 - 345   2009年

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  • 慢性腎臓病(CKD)の臨床的問題とCKD対策への取り組み.

    前島洋平, 槇野博史

    実験医学   27 ( 9 )   1412 - 1417   2009年

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  • INNOVATION.

    小川大輔, 槇野博史

    DATAUPDATE(循環系第4版)   270 - 271   2009年

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  • Evidence-based Practice Guideline for the Treatment of CKD.

    Maeshima Y, Makino H

    Clin Exp Nephrol   13 ( 3 )   187 - 248   2009年

     詳細を見る

  • INNOVATION.

    小川大輔, 槇野博史

    Nephrology Frontier   8 ( 2 )   62 - 63   2009年

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  • 腎臓専門医での診断とかかりつけ医への逆紹介の要点 4.糖尿病腎症の確定診断はどのように行うのですか?.

    小寺 亮, 四方賢一, 槇野博史

    かかりつけ医と専門医のためのCKD診療ガイド   73 - 77   2009年

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  • 糖尿病とCKD.

    斎藤大輔, 前島洋平, 槇野博史

    カラー版 糖尿病学 基礎と臨床 アップデート版Ⅰ   128 - 133   2009年

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  • Ⅲ章 糖尿病患者の透析管理のポイント 1.血糖のコントロール C.薬物療法(インスリン,SU薬など).

    梶谷展生, 槇野博史

    糖尿病透析患者診療・ケアハンドブック   39 - 45   2009年

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  • Ⅲ章 糖尿病患者の透析管理のポイント 1.血糖のコントロール B.食事療法.

    梶谷展生, 槇野博史

    糖尿病透析患者診療・ケアハンドブック   33 - 38   2009年

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  • CKD診療における高血圧治療のポイント.

    井上達之, 杉山 斉, 槇野博史

    PHYSICIANS’ THERAPY MANUAL   1   1 - 2   2009年

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  • 腎炎、腎症の免疫抑制療法 タクロリムス.

    山中龍太郎, 佐田憲映, 槇野博史

    腎と透析   66 ( 6 )   937 - 939   2009年

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  • 故大藤眞先生を偲んで.

    槇野博史

    日本腎臓学会誌   51 ( 5 )   503 - 505   2009年

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  • 日米におけるCKD啓発の意義と管理の重要性.

    槇野博史

    Nikkei Medical 腎臓のプライマリケア   38 - 41   2009年

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  • インタビュー CKDは1330万人、専門医だけでは診きれない.

    槇野博史

    Nikkei Medical 腎臓のプライマリケア   3 - 11   2009年

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  • 2型糖尿病患者におけるインスリングラルギンあるいは中間型インスリンから二相性インスリンアナログ製剤(ノボラピッド30ミックス注)への切り替え効果.

    小川大輔, 槇野博史

    Progress in Medicine   29 ( 8 )   2067 - 2070   2009年

     詳細を見る

  • 特集:慢性腎臓病(CKD)対策の現状と今後―CKD診療ガイドラインを中心に― 4.CKDの治療と管理のポイント 4)CKDと糖尿病.

    前島洋平, 槇野博史

    Progress in Medicine   29 ( 8 )   1943 - 1948   2009年

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  • 糖尿病性腎症の透析導入のタイミング.

    高取優二, 中尾一志, 槇野博史

    腎と透析   67 ( 2 )   215 - 218   2009年

     詳細を見る

  • 回答 eGFRと血清クレアチニンの関係.

    前島洋平, 槇野博史

    日本医事新報   ( 4452 )   75 - 76   2009年

     詳細を見る

  • 増える糖尿病性腎症 気づかず進行!発見の決めては?.

    槇野博史

    NHKテレビテキスト きょうの健康   9   88 - 95   2009年

     詳細を見る

  • リスクを防ぐ! CKDのきほん.

    勅使河原早苗, 和田 淳, 槇野博史

    メタボリックシンドロームぷらす   96 - 108   2009年

     詳細を見る

  • 診療controversy medical decision makingのために 糖尿病腎症に対する蛋白制限●推進の立場から.

    小川大輔, 槇野博史

    内科   104 ( 3 )   551 - 555   2009年

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  • 第24回日本糖尿病合併症学会の開催に当たって 糖尿病合併症治療に向けた新たなる展開.

    槇野博史

    MEDICAMENT NEWS   ( 1990 )   11 - 11   2009年

     詳細を見る

  • 増える糖尿病性腎症悪化させない!万全治療.

    槇野博史

    NHKきょうの健康9   92 - 95   2009年

     詳細を見る

  • 追悼コラム-故大藤眞先生を偲んで-.

    槇野博史

    NEWS LETTER リウマチ   23   22 - 22   2009年

     詳細を見る

  • シンポジウム 3.糖尿病の血管合併症とトータルケア:早期診断、そして予防へ 2)糖尿病性腎症.

    槇野博史

    日本内科学会雑誌   98 ( 9 )   2216 - 2222   2009年

     詳細を見る

  • 自覚症状がなかなか出ない糖尿病性腎症あなたは大丈夫?.

    槇野博史

    STERA NHKウィークリーステラ   100 - 100   2009年

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  • 我が国におけるCKDの現況とその対策.

    槇野博史

    腎不全看護 Seminar Report   15 - 17   2009年

     詳細を見る

  • CKDの治療戦略と今後の展望.

    槇野博史

    血圧   16 ( 11 )   75 - 79   2009年

     詳細を見る

  • わが国のCKD対策の現状と課題―日本腎臓病学会におけるCKD対策とかかりつけ医との連携.

    槇野博史

    日本医師会雑誌   138 ( 8 )   1501 - 1515   2009年

     詳細を見る

  • エビデンスに基づくCKD診療ガイドライン2010.

    前島洋平, 槇野博史

    日本腎臓学会誌   51 ( 8 )   905 - 1066   2009年

     詳細を見る

  • 岡山地区の腎臓を守るためには今、何をすべきか.

    槇野博史

    血圧   16 ( 11 )   95 - 101   2009年

     詳細を見る

  • 微量アルブミン尿と心血管イベントの関係.

    槇野博史

    メディカルビューポイント(MVP)   30 ( 11 )   5 - 5   2009年

     詳細を見る

  • Ⅻ.日本人の大規模臨床試験.

    小川大輔, 槇野博史

    日本臨床   67 ( 7 )   673 - 676   2009年

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  • 糖尿病教育入院患者におけるうつ病の評価.

    小川大輔, 槇野博史

    Therapeutic Research   30 ( 11 )   1883 - 1887   2009年

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  • 糖尿病性腎症:Pointofnoreturnは?.

    小川大輔, 槇野博史

    Medicina   46 ( 13 )   1968 - 1972   2009年

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  • 名医のセカンドオピニオン 透析増加にストップを 早期発見のカギは検尿.

    槇野博史

    週刊朝日増刊号   23 - 23   2009年

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  • 腎不全合併症の成因と新たな治療戦略.

    槇野博史

    BIO Clinica   24 ( 14 )   16 - 17   2009年

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  • 腎疾患進行抑制と高血圧治療―アリスキレンの可能性―.

    槇野博史

    血圧   16 ( 12 )   75 - 81   2009年

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  • Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

    Mina Takahashi, Fumio Otsuka, Tomoko Miyoshi, Hiroyuki Otani, Junko Goto, Misuzu Yamashita, Toshio Ogura, Hirofumi Makino, Hiroyoshi Doihara

    JOURNAL OF ENDOCRINOLOGY   199 ( 3 )   445 - 455   2008年12月

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    記述言語:英語   出版者・発行元:BIOSCIENTIFICA LTD  

    Estrogen is involved in the development and progression of breast cancer. Here, we investigated the effects of bone morphogenetic proteins (BMPs) on breast cancer cell proliferation caused by estrogen using human breast cancer MCF-7 cells. MCF-7 cells express estrogen receptors (ESR1 and ESR2), BMP receptors, and SMAD signaling molecules. Estradiol and membrane-impermeable estradiol stimulated MCF-7 cell proliferation. Estradiol also reduced mRNA levels of ESP1, aromatase, and steroid sulfatase. Treatment with BMPs and activin had no effects on MCF-7 cell proliferation. However, BMP2, BMP4, BMP6, BMP7, and activin suppressed estradiol-induced cell mitosis, with the effects of BMP6, BMP7, and activin being more prominent than those of BMP2 and BMP4. Activin decreased ESR1 mRNA expression, while BMP6 and BMP7 impaired steroid sulfatase expression in MCF-7 cells. Interestingly, SMAD1,5,8 activation elicited by BMP6 and BMP7, but not by BMP2 and BMP4, was preserved even under the exposure of a high concentration of estradiol. The difference of BMP responsiveness was likely due to the differential modulation of BMP receptor expression induced by estradiol. In this regard, estradiol decreased the expression levels of BMPR1A, BMPR1B, ACVR2A, and ACVR2B but did not affect ACVR1 and BMPRII, leading to the sustained effects of BMP6 and BMP7 in estrogen-treated MCF-7 cells. Estradiol rapidly activated MAPK phosphorylation including extracellular signal-regulated kinase 1/2, p38, and stress-activated protein kinase/c-Jun NH2-terminal kinase pathways and BMP6, BMP7, and activin preferentially inhibited estradiol-induced p38 phosphorylation. SB203580, a selective p38 MAPK inhibitor effectively suppressed estradiol-induced cell mitosis, suggesting that p38 MAPK plays a key role in estrogen-sensitive breast cancer cell proliferation. Thus, a novel interrelationship between estrogen and the breast cancer BMP system was uncovered, in which inhibitory effects of BMP6 and BMP7 on p38 signaling and steroid sulfatase expression were functionally involved in the suppression of estrogen-induced mitosis of breast cancer cells.

    DOI: 10.1677/JOE-08-0226

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  • Proposal of podocytic infolding glomerulopathy as a new disease entity: a review of 25 cases from nationwide research in Japan

    Kensuke Joh, Takashi Taguchi, Hidekazu Shigematsu, Yutaka Kobayashi, Hiroshi Sato, Shinichi Nishi, Ritsuko Katafuchi, Shinsuke Nomura, Yoshihide Fujigaki, Yasunori Utsunomiya, Hitoshi Sugiyama, Takao Saito, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   12 ( 6 )   421 - 431   2008年12月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Background A rare and peculiar glomerulopathy has begun to be recognized in Japan. The Japanese Society of Nephrology has established a research working group and has collected cases from all over Japan in an attempt to understand the complete spectrum of this glomerulopathy.
    Method The diagnostic criterion, which was needed to collect the cases, was proposed as a glomerulopathy showing microspheres or microtubular structures or both associated with podocytic infolding into the glomerular basement membrane (GBM) on electron microscopy. The lesion shows a non-argentaffin hole in the GBM with periodic acid methenamine silver staining and is similar to membranous glomerulonephritis.
    Results Twenty-five cases were collected from 17 institutions. Patients were 20-69 years old (19 women, 6 men). Seventeen patients also had collagen diseases such as lupus nephritis and Sjogren's syndrome. All patients had proteinuria. Proteinuria showed a remission in 15 of 23 patients within 12 months, but proteinuria remained higher than 1.0 g/day in five patients despite different types of therapy. Podocytic infolding including microspheres showed either positive or negative staining for immunoglobulins. Cluster formation of microspheres was found in 4 of 17 patients with collagen disease, and in five out eight patients without collagen disease. Electron-dense deposits in the GBM were also found in 6 of 17 patients with collagen disease but were not found in eight patients without collagen disease.
    Conclusion Some patients might have a subtype of lupus nephritis, class V, or membranous glomerulonephritis. However, we propose a new disease entity, podocytic infolding glomerulopathy, as a common basis of all 25 patients, because we suspect that microspheres or microtubular structures or both can be derived from podocytic infolding.

    DOI: 10.1007/s10157-008-0104-z

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  • Unique microstructures and podocytic infolding in glomerular basement membrane associated with collagen diseases: a report of three cases

    Hitoshi Sugiyama, Mie Maruyama, Hiroshi Morinaga, Tatsuyuki Inoue, Kei-ichi Takiue, Yoko Kikumoto, Masaru Kinomura, Ken-ei Sada, Shigeru Akagi, Shinji Kitamura, Yohei Maeshima, Hirofumi Makino

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   12 ( 6 )   450 - 454   2008年12月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Unique renal histopathological appearances, consisting of podocytic infolding and microstructures in the glomerular basement membrane (GBM) were identified in the renal biopsies from three patients with collagen diseases such as systemic lupus erythematosus (lupus nephritis, class II) and Sjogren's syndrome. In each case, the GBM contained microstructures, including microspheres and microtubular structures, accompanied by podocytic infolding into the GBM when examined by electron microscope. The size of the microstructures in the GBM ranged from 40 to 160 nm. Glomerular endothelial cells also seemed to be infolded in the GBM in a case with lupus nephritis. The response to glucocorticoid therapy was favorable in two cases. The cause of these morphological changes in the GBM might be associated with autoimmune disorders.

    DOI: 10.1007/s10157-008-0098-6

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  • Bilateral dystonia in type 1 diabetes: A case report

    Akihiro Yasuhara, Jun Wada, Hirofumi Makino

    Journal of Medical Case Reports   2   352   2008年11月

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    記述言語:英語  

    Introduction: Diabetic hemichorea-hemiballismus is a rare complication of type 2 diabetes. Here, we report a case with type 1 diabetes, with hemichorea and bilateral dystonia manifested as hyperglycemia-induced involuntary movement. Case presentation: A 62-year-old Japanese women with body weight loss of 30 kg during the past year developed symptoms of thirst, polydipsia and polyuria. She also presented with hemichorea and bilateral dystonia for 5 days and extremely high plasma glucose (774 mg/dl), hemoglobin A1c (21.2%) and glycated albumin (100%) with ketosis. Based on the presence of glutamic acid decarboxylase antibodies (18,000 U/ml
    normal &lt
    1.3 U/ ml), low daily urinary excretion of C-peptide (7.8 μg), ketosis and human leucocyte antigen typing DR-4, we diagnosed type 1 diabetes mellitus. We treated the patient with a continuous intravenous regular insulin infusion and medication with haloperidol, and dystonia completely disappeared within 3 days. Conclusion: Hyperglycemia-induced involuntary movement is one of the manifestations of dystonia and hemichorea-hemiballism. © 2008 Yasuhara et al
    licensee BioMed Central Ltd.

    DOI: 10.1186/1752-1947-2-352

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  • Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide-Sensitive Factor Attachment Protein Receptor Complex

    Akihiro Yasuhara, Jun Wada, Sandra M. Malakauskas, Yanling Zhang, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Motoko Kanzaki, Sanae Teshigawara, Kazuya Yamagata, Thu H. Le, Hirofumi Makino

    CIRCULATION   118 ( 21 )   2146 - 2155   2008年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background-Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1 alpha and-1 beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins.
    Methods and Results-Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na(+) channel, and H(+)-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 mu mol/L aldosterone in mIMCD-3 cells.
    Conclusions-Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension. (Circulation. 2008; 118: 2146-2155.)

    DOI: 10.1161/CIRCULATIONAHA.108.787259

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  • Renal pathology of ANCA-related vasculitis: proposal for standardization of pathological diagnosis in Japan

    Kensuke Joh, Eri Muso, Hidekazu Shigematsu, Masato Nose, Michio Nagata, Yoshihiro Arimura, Wako Yumura, Takashi Wada, Kousaku Nitta, Hirofumi Makino, Yoshio Taguma, Hidetoshi Kaneoka, Yuhsuke Suzuki, Masaki Kobayashi, Akio Koyama, Joichi Usui, Hiroshi Hashimoto, Shoichi Ozaki, Yasuhiko Tomino, Kunihiro Yamagata

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   12 ( 4 )   277 - 291   2008年8月

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    記述言語:英語   出版者・発行元:SPRINGER  

    Background In Japan, systematic evaluation of the histologic parameters of anti-neutrophil cytoplasmic auto-antibodies ( ANCA)-related vasculitis has been performed according to the Japanese classification by Shigematsu et al. However, this classification is quite different from that of the European Vasculitis Study Group (EUVAS) classification. Therefore, a histological common basis is needed to compare Japanese histological data with the international database.
    Method Histological parameters concerning glomerular, tubulointerstitial, and vascular lesions of ANCA-related vasculitis, which are indispensable for clinical management, were elucidated and defined by reviewing, utilizing the merits of, and amending the two scoring systems.
    Results and conclusion A new comprehensive and standardized scoring system, by which histological quantitative assessment can provide evidence for therapy planning, has been developed for renal biopsy of Japanese ANCA-related vasculitis.

    DOI: 10.1007/s10157-008-0052-7

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  • Aldosterone breakthrough caused by chronic blockage of angiotensin II type 1 receptors in human adrenocortical cells: Possible involvement of bone morphogenetic protein-6 actions

    Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Jiro Suzuki, Tomoko Miyoshi, Yoshihiro Kano, Junko Goto, Toshio Ogura, Hirofumi Makino

    ENDOCRINOLOGY   149 ( 6 )   2816 - 2825   2008年6月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    Circulating aldosterone concentrations occasionally increase after initial suppression with angiotensin II (Ang II) converting enzyme inhibitors or Ang II type 1 receptor blockers (ARBs), a phenomenon referred to as aldosterone breakthrough. However, the underlying mechanism causing the aldosterone breakthrough remains unknown. Here we investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6, which is expressed in adrenocortical cells, enhances Ang II-but not potassium-induced aldosterone production in human adrenocortical cells. Accordingly, we examined the roles of BMP-6 in aldosterone breakthrough induced by long-term treatment with ARB. Ang II stimulated aldosterone production by adrenocortical cells. This Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis and CYP11B2 expression were attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartanpretreated cells. Levels of Ang II type 1 receptor mRNA were not changed by chronic candesartan treatment. However, BMP-6 enhancement of Ang II- induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation, and BRE-Luc activity was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors activin receptor-like kinase-2 and activin type II receptor mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB. (

    DOI: 10.1210/en.2007-1476

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  • Glycated albumin levels predict long-term survival in diabetic patients undergoing haemodialysis

    Kousuke Fukuoka, Kazushi Nakao, Hisanori Morimoto, Ai Nakao, Yuji Takatori, Katsuhiko Arimoto, Masafumi Taki, Jun Wada, Hirofumi Makino

    NEPHROLOGY   13 ( 4 )   278 - 283   2008年6月

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    記述言語:英語   出版者・発行元:BLACKWELL PUBLISHING  

    Aim: Glycated albumin (GA) is recognized as a reliable marker for monitoring glycemic control particularly in patients with end-stage renal disease (ESRD). Here, we investigated the impact of GA levels on long-term survival in diabetic patients with ESRD.
    Methods: We enrolled ESRD patients with diabetic nephropathy into our single-centre prospective follow-up study (n = 98, 66 men and 32 women; age 68.2 +/- 12.3 years) with a mean follow-up period of 47.7 months. All patients had started haemodialysis between December 1992 and November 2003. They were categorized into two groups according to their GA levels at the initiation of haemodialysis; GA < 29% (low-GA group; n = 54) and GA >= 29% (high-GA group; n = 44).
    Results: Between low-GA and high-GA groups, there were no significant differences in various clinical parameters except GA and HbA1c levels. The cumulative survival rate of low-GA group was significantly higher than that of high-GA group (P = 0.034, log-rank test). After adjustment for age, sex, total cholesterol, C-reactive protein and albumin, high-GA was a significant predictor of survival (hazard ratio 1.042 per 1.0% increment of GA, 95% Cl 1.014-1.070, P < 0.05), but not in the case with HbA1c. Cox proportional hazard model demonstrated that high-GA group was a significant predictor for cardiovascular death (hazard ratio 2.971 (1.064-8.298), P = 0.038).
    Conclusion: We conclude that poor glycemic control (GA >= 29%) before starting haemodialysis is associated with increased cardiovascular morbidity and shortened survival in diabetic patients with ESRD.

    DOI: 10.1111/j.1440-1797.2007.00864.x

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  • Procollagen c-proteinase enhancer-1 (PCPE-1) interacts with β2-microglobulin (β2-m) and may help initiate β2-m amyloid fibril formation in connective tissues.

    Morimoto H, Wada J, Font B, Mott JD, Hulmes DJS, Ookoshi T, Naiki H, Yasuhara A, Nakatsuka A, Fukuoka K, Takatori Y, Ichikawa H, Akagi S, Nakao K, Makino H

    Matrix Biology   27 ( 3 )   211 - 219   2008年4月

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  • Comparison of serum uric acid levels between Japanese with and without metabolic syndrome

    Takeyuki Numata, Nobuyuki Miyatake, Jun Wada, Hirofumi Makino

    Diabetes Research and Clinical Practice   80 ( 1 )   -e5   2008年4月

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    記述言語:英語  

    Objective: The link between uric acid levels and metabolic syndrome was investigated. Methods: We used data for 997 men and 1290 women. Metabolic syndrome was defined by a new criterion in Japan and uric acid was measured. Results: Subjects who did not drink alcohol were evaluated. Uric acid was significantly higher in subjects with metabolic syndrome compared with subjects without the syndrome in both sexes. The presence of abdominal obesity and dyslipidemia in men and abdominal obesity in women revealed positive impacts on uric acid levels. Conclusion: High serum uric acid may be often associated with metabolic syndrome in Japanese people, which accelerates the development of cardiovascular disease from metabolic syndrome. © 2007 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.diabres.2007.10.031

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  • Involvement of bone morphogenetic protein-4 in GH regulation by octreotide and bromocriptine in rat pituitary GH3 cells

    Tomoko Miyoshi, Fumio Otsuka, Hiroyuki Otani, Kenichi Inagaki, Junko Goto, Misuzu Yamashita, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

    JOURNAL OF ENDOCRINOLOGY   197 ( 1 )   159 - 169   2008年4月

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    記述言語:英語   出版者・発行元:SOC ENDOCRINOLOGY  

    Here we investigated roles of the pituitary bone morphogenetic protein (BMP) system in modulating GH production regulated by a somatostatin analog, octreotide (OCT) and a dopamine agonist, bromocriptine (BRC) in rat pituitary somatolactotrope tumor GH3 cells. The GH3 cells were found to express BMP ligands, including BMP-4 and BMP-6-1 BMP type-1 and type-2 receptors (except the type-1 receptor, activin receptor-like kinase (ALK)-6); and Smad signaling molecules. Forskolin stimulated GH production in accordance with cAMP synthesis. BRC, but not OCT, suppressed forskolin-induced cAMP synthesis by GH3 cells. Individual treatment with OCT and BRC reduced forskolin-induced GH secretion. A low concentration (0-1 mu M) of OCT in combination with BRC (1-100 mu M) exhibited additive effects on reducing GH and cAMP production induced by forskolin. However, a high concentration (10 mu M) of OCT in combination with BRC failed to suppress GH and cAMP production. BMP-4 specifically enhanced GH secretion and cAMP production induced by forskolin in GH3 cells. BRC, but not OCT, inhibited BMP4-induced activation of Smad1,5,8 phosphorylation and Id-1 transcription and decreased ALK-3 expression. Of note, in the presence of a high concentration of OCT, the BRC effects suppressing BMP-4-Smad1,5,8 signaling were significantly impaired. In the presence of BMP-4, a high concentration of OCT also attenuated the BRC effects suppressing forskolin-induced GH and cAMP production. Collectively, a high concentration of OCT interferes with BRC effects by reducing cAMP production and suppressing BMP-4 signaling in GH3 cells. These findings may explain the mechanism of resistance of GH reduction to a combination therapy with OCT and BRC for GH-producing pituitary adenomas.

    DOI: 10.1677/JOE-07-0549

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  • Simvastatin antagonizes tumor necrosis factor-α inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating smad signaling and Ras/Rho-mitogen-activated protein kinase pathway.

    Yamashita M, Otsuka F, Mukai T, Otani H, Inagaki K, Miyoshi T, Goto J, Yamamura M, Makino H

    Journal of Endocrinology   196 ( 3 )   601 - 613   2008年3月

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  • A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy

    Masaru Kinomura, Hitoshi Sugiyama, Takao Saito, Akira Matsunaga, Ken-ei Sada, Motoko Kanzaki, Yuki Takazawa, Yohei Maeshima, Hiroyuki Yanai, Hirofumi Makino

    NEPHROLOGY DIALYSIS TRANSPLANTATION   23 ( 2 )   751 - 756   2008年2月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    DOI: 10.1093/ndt/gfm675

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  • A rare tumor in the adrenal region: Neuron-specific enolase (NSE)-producing leiomyosarcoma in an elderly hypertensive patient

    Junko Goto, Fumio Otsuka, Ryo Kodera, Tomoko Miyoshi, Masaru Kinomura, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hiroyuki Yanai, Yasutomo Nasu, Hirofumi Makino

    ENDOCRINE JOURNAL   55 ( 1 )   175 - 181   2008年2月

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    記述言語:英語   出版者・発行元:JAPAN ENDOCRINE SOC  

    A 73-year-old Japanese woman was referred for examination of right flank pain and progressive hypertension. Abdominal CT incidentally detected a right adrenal mass 8 cm in size. The tumor exhibited isodensity by CT and contained high-intense lesion by T2-weighted MRI. Scintigraphy with I-131-metaiodobenzylguanidine and I-131-adosterol showed no abnormal uptake by whole body scan. Positron emission tomography scan with F-18-2-fluoro-D-deoxyglucose demonstrated an exclusive uptake in the right adrenal mass. Adrenocortical hormone levels and catecholamine secretion were within normal range; however, the level of serum neuron-specific enolase (NSE) was found to be markedly high. After controlling systemic blood pressure with an alpha 1-blocker, the right adrenal tumor was surgically removed, along with the right kidney and inferior vena cava which adhered to it. The tumor was pathologically proven to be leiomyosarcoma, which was immunohistochemically positive with a-smooth muscle actin and negative with CD57, S-100 and c-kit proteins. Notably, NSE protein was massively expressed in the resected tumor. After surgery blood pressure was controlled with regular medication and serum NSE levels have since normalized. The possibility of leiomyosarcoma should be kept in mind in adrenal incidentalomas with rapid growth and atypical radiological images. Our findings suggest that circulating NSE levels may be clinically useful for early detection of recurrence.

    DOI: 10.1507/endocrj.K07E-020

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  • Chronic kidney disease perspectives in Japan and the importance of urinalysis screening

    Kunihiro Yamagata, Kunitoshi Iseki, Kousaku Nitta, Hirokazu Imai, Yasuhiko Iino, Seiichi Matsuo, Hirofumi Makino, Akira Hishida

    CLINICAL AND EXPERIMENTAL NEPHROLOGY   12 ( 1 )   1 - 8   2008年2月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:SPRINGER  

    There are racial differences in primary renal diseases for end-stage renal disease (ESRD) and the incidence and prevalence of cardiovascular disease (CVD). To reduce the number of patients with both ESRD and CVD, an effective screening method for CKD should be established. In Japan, screening with the urine dip-stick test for proteinuria has been used since 1972 targeting every child and worker and since 1983 for every resident over 40 years old. There are several reasons for continuing this screening program. First, the positive rate of proteinuria is high in the Japanese general population, especially subjects with neither hypertension nor diabetes. Most of these subjects have no symptoms, and the only sign of renal disease is asymptomatic urinary abnormalities. Second, the prevalence and incidence of glomerulonephritis, especially IgA nephropathy, are high in the Japanese and Asian races, and urinalysis is the only method for early detection of chronic glomerulonephritis. Third, 10-year survival of the ESRD patients due to glomerulonephritis was approximately twice that of ESRD patients due to diabetes and nephrosclerosis. Consequently, reducing the incidence of ESRD due to glomerulonephritis is one of the best ways to reduce the prevalence of ESRD. Furthermore, higher incidence of ESRD in Asian races than in Caucasians was reported. Proteinuria is known to be the best predictor for reducing renal function, and the urine dip-stick test for proteinuria is less expensive and is cost-effective. For an effective screening strategy to reduce the ESRD population in Japanese and Asians, universal screening with the urine dipstick test for proteinuria could be one solution.

    DOI: 10.1007/s10157-007-0010-9

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  • The MUSCAT study: A Multicenter PROBE study comparing the effects of angiotensin II type-1 receptor blockers on self-monitored home blood pressure in patients with morning hypertension: Study design and background characteristics

    Haruhito Uchida, Yoshio Nakamura, Masanobu Kaihara, Hisanao Norii, Yoshihisa Hanayama, Hirofumi Makino

    HYPERTENSION RESEARCH   31 ( 1 )   51 - 58   2008年1月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Elevated morning home blood pressure (MHBP) has been reported to have a close relationship to cerebro-cardiovascular events and hypertensive target organ damages, and hence is regarded as a predictor of cardiovascular events. However, there is no evidence that lowering of MHBP can improve morbidity, mortality or target organ damage. In recent guidelines, angiotensin II type-1 receptor blockers (ARBs) are recommended as the first-choice drugs for antihypertensive therapy. Pharmacological characteristics differ among ARBs, and some are suggested to have greater efficacy in lowering MHBP than others. In preparation for the MUSCAT study, we surveyed both self-monitored MHBP and office blood pressure (OBP) in 1,234 patients with essential hypertension. Among them, 367 patients had diabetes mellitus (DM) and 229 suffered from chronic kidney disease (CKD). More than 64% (n=790) of patients had morning hypertension. In MUSCAT, we will investigate the different effects of four ARBs (losartan, candesartan, valsartan, and telmisartan) in patients with morning hypertension, with a focus on the drugs' MHBP-lowering efficiency. Secondly, we will evaluate the different actions of the four ARBs on cardiovascular surrogate markers, such as the brachial-ankle pulse wave velocity, high-sensitive C-reactive protein level, and urinary albumin excretion/creatinine ratio. Patients will be randomized into four arms, and given one of the four "sartans" once daily for 12 months. MHBPs and surrogate markers will be examined at baseline and after 1 year of follow-up. In the stratified analysis, we will determine the significance of MHBP reduction on cardiovascular risk management.

    DOI: 10.1291/hypres.31.51

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  • 腎機能評価 早期発見のための検尿の意義.

    瀧上慶一, 杉山 斉, 槇野博史

    治療(J.Therap.)   90 ( 4 )   1424 - 1428   2008年

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  • Ⅱ腎症モデル.

    佐々木基史, 四方賢一, 槇野博史

    Diabetes Frontier   18 ( 5 )   531 - 534   2008年

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  • わが国のCKDを取り巻く学術的協力体制.

    井上達之, 槇野博史

    臨牀と研究   84 ( 11 )   1539 - 1544   2008年

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  • 高血糖、たんぱく尿は早期治療を.

    槇野博史

    日経ビジネス   62   2008年

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  • 慢性腎臓病における尿細管間質障害の意義.

    木野村賢, 杉山 斉, 槇野博史

    医学のあゆみ   225 ( 4 )   281 - 284   2008年

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  • 慢性腎臓病:CKD最新の診療 蛋白尿の減少の意義と実際.

    前島洋平, 槇野博史

    Modern Physician   28 ( 8 )   1175 - 1178   2008年

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  • BMP-6による副腎皮質アルドステロン分泌調整機構とアルドステロンブレイクスルー現象への関与.

    大塚文男, 大谷寛之, 稲垣兼一, 鈴木二郎, 三好智子, 小倉俊郎, 槇野博史

    Aldosterone.jp 日本心血管内分泌代謝学会レポート   2008年

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  • 慢性腎臓病:CKD最新の診療 早期診断による心・血管障害の予防と腎不全への進展阻止 巻頭言:今なぜCKD対策が重要なのか?.

    槇野博史

    Modern Physician   28 ( 8 )   1133   2008年

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  • 座談会 食塩と高血圧 日本人の高血圧治療に新たな可能性を拓く選択的アルドステロンブロッカー(SAB).

    槇野博史, 大塚文男

    Medical Tribune   2   1 - 4   2008年

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  • 透析療法を受けると気分が悪くなります

    槇野博史

    NHKテレビテキスト きょうの健康   ( 9 )   132   2008年

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  • 医療経済効果を考慮した糖尿病性腎症にみるテルミサルタンの有用性.

    槇野博史

    Pharma Medica   26 ( 9 )   90 - 91   2008年

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  • 腎臓・尿酸代謝とメタボリックシンドローム.

    黒瀬祐子, 和田 淳, 槇野博史

    アディポサイエンス19   5 ( 3 )   233 - 236   2008年

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  • 糖尿病関連諸検査―測定法、臨床的意義、評価法― 尿検査 尿中L-PGDS.

    吉川理津子, 和田 淳, 槇野博史

    日本臨牀   66 ( 4 )   438 - 441   2008年

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  • CKD(慢性腎臓病)対策における食事療法の重要性.

    槇野博史

    キッセイゆめ通信   27   1月4日   2008年

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  • 糖尿病血管合併症を予防するためのチーム医療―腎症に対する集約的治療の試み―.

    四方賢一, 槇野博史

    糖尿病合併症   22 ( 1 )   59 - 62   2008年

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  • 糖尿病と腎腫大.

    中司敦子, 和田 淳, 槇野博史

    腎と透析   65 ( 1 )   9 - 14   2008年

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  • 血圧管理.

    高取優二, 中尾一志, 槇野博史

    Diabetes Frontier   19 ( 6 )   754 - 757   2008年

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  • 高齢糖尿病患者の夜間血圧とアルブミン尿.

    小寺 亮, 四方賢一, 槇野博史

    血圧   15 ( 9 )   740 - 741   2008年

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  • 治療戦略の優先順位付けのジレンマー糖尿病と腎疾患ー.

    森永裕士, 佐田憲映, 槇野博史

    Medicina   45 ( 9 )   1598 - 1603   2008年

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  • 慢性腎臓病の治療総論(降圧療法、食事療法を含めて).内科シリーズ:ガイドライン.

    井上達之, 杉山 斉, 槇野博史

    岡山医学会雑誌   120   215 - 218   2008年

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  • 慢性腎臓病:CKD最新の診療 早期診断による心・血管障害の予防と腎不全への進展阻止 血管炎症候群/MPA.

    斉藤大輔, 佐田憲映, 槇野博史

    Modern Physician   28 ( 8 )   1215 - 1220   2008年

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  • Remissionをめざした治療 血管炎症候群/MPA.

    斎藤大輔, 佐田憲映, 槇野博史

    Modern Physician   28 ( 8 )   1215 - 1220   2008年

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  • 感染症.治療:CKD進展リスクファクター対策

    赤木 滋, 杉山 斉, 槇野博史

    日本臨床   66   1794 - 1798   2008年

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  • ループス腎炎の新組織分類による治療.

    佐田憲映, 槇野博史

    2008年

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  • ループス腎炎の新病理分類.

    古城昭一郎, 佐田憲映, 槇野博史

    臨床検査   52 ( 5 )   565 - 568   2008年

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  • アンジオテンシンⅡ受容体阻害によるヒト副腎皮質細胞でのアルドステロンブレイクスルーの発生とBMP-6の関与.

    大塚文男, 大谷寛之, 稲垣兼一, 鈴木二郎, 三好智子, 後藤順子, 塚本尚子, 小倉俊郎, 槇野博史

    Aldosterone.   2008年

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  • 糖尿病性腎症とは.

    小川大輔, 槇野博史

    Examination Today   3   2008年

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  • 糖尿病透析患者の病態と対策.

    福岡晃輔, 中尾一志, 槇野博史

    最新透析医学   389 - 394   2008年

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  • マクロファージスカベンジャー受容体(SR-A)は炎症を制御することにより糖尿病性腎症を抑制する―平成19年度岡山医学会賞(結城賞)受賞論文―.

    片岡仁美, 四方賢一, 佐々木基史, 槇野博史

    岡山医学会雑誌   120   143 - 147   2008年

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  • 慢性腎臓病の治療総論(糖尿病腎症、貧血管理、薬物治療の注意点など).

    森永裕士, 杉山 斉, 槇野博史

    岡山医学会雑誌   120 ( 11 )   337 - 341   2008年

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  • Amelioration of cisplatin-induced acute renal injury by renal progenitor-like cells derived from the adult rat kidney

    Masaru Kinomura, Shinji Kitamura, Katsuyuki Tanabe, Kunihiro Ichinose, Kumiko Hirokoshi, Yuki Takazawa, Hiroyuki Kitayama, Tatsuyo Nasu, Hitoshi Sugiyama, Yasushi Yamasaki, Takeshi Sugaya, Yohei Maeshima, Hirofumi Makino

    CELL TRANSPLANTATION   17 ( 1-2 )   143 - 158   2008年

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    記述言語:英語   出版者・発行元:COGNIZANT COMMUNICATION CORP  

    The replacement of a necrotic tubular epithelium with functional tubular epithelial cells is required for recovery from acute renal failure (ARF). A rat renal progenitor-like (rKS56) cell line was recently established derived from the S3 segment of renal proximal tubules. The therapeutic efficacy of rKS56 cells was examined in a rat model of cisplatin-induced ARE rKS56-lacZ cells expressing P-galactosidase were injected into SD rats either at the subcapsule of the left kidney (rKS-SC) or via the left renal artery (rKS-IA) 2 days after the injection of cisplatin. Bluo-gal(+) rKS56-lacZ cells were observed in the subcapsule in the rKS-SC group on day 5, and were further increased in number on day 9, accompanied by partial distribution in the corticomedullary junction, but not in the rKS-IA group. A portion of Bluo-gal(+) cells coexpressed Ki-67, aquaporin-1, hepatocyte growth factor (HGF), and c-Met. rKS-SC treatment significantly improved the tubular injury scores, ameliorated tubular cell apoptosis, and induced cell proliferation. The renal function also significantly improved in the rKS-SC group on day 5. These results demonstrate that locally implanted rKS56 cells could differentiate into tubular epithelial cells, thereby accelerating the recovery from tubular injury, most likely by producing tubular trophic factors. These results suggest the therapeutic potential of this novel approach for patients with end-stage renal failure.

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  • Increased susceptibility to oxidant-mediated tissue injury and peritoneal fibrosis in acatalasemic mice

    Naomi Fukuoka, Hitoshi Sugiyama, Tatsuyuki Inoue, Yoko Kikumoto, Kei-ichi Takiue, Hiroshi Morinaga, Kazushi Nakao, Yohei Maeshima, Masato Asanuma, Da-Hong Wang, Keiki Ogino, Noriyoshi Masuoka, Hirofumi Makino

    AMERICAN JOURNAL OF NEPHROLOGY   28 ( 4 )   661 - 668   2008年

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    記述言語:英語   出版者・発行元:KARGER  

    Background: Peritoneal fibrosis is a major complication leading to the loss of peritoneal function in patients undergoing peritoneal dialysis. However, the effect of catalase depletion on peritoneal fibrosis has not yet been investigated. Methods: The impact of catalase deficiency on progressive peritoneal fibrosis has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of chlorhexidine gluconate (CG) every other day for 14 days. Results: The CG injections resulted in a thicker peritoneal membrane, reflecting peritoneal fibrosis with accumulation of interstitial type I collagen, peritoneal deposition of lipid peroxidation products (4-hydroxy-2-nonenal and 4-hydroxy-2-hexenal), and an elevated level of 8-hydroxy-2'-deoxyguanosine in peritoneal fluid in both mouse groups on day 14. The extent of these changes, however, was significantly higher in acatalasemic mice than in wild-type mice. The level of catalase activity remained low in the acatalasemic peritoneum without the compensatory upregulation of glutathione peroxidase, but with an insufficient upregulation of superoxide dismutase activity in CG-injected mice. Conclusions: Acatalasemia, therefore, exacerbates oxidant tissue injury and induces the peritoneum to develop irreversible fibrosis which is the most important complication of peritoneal dialysis. This study suggests that catalase plays a crucial role in the defense against oxidant-mediated peritoneal injury in a mouse peritoneal fibrosis model. Copyright (C) 2008 S. Karger AG, Basel.

    DOI: 10.1159/000121357

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  • 甲状腺機能低下症により顕在化したApparent Mineralocorticoid Excess (AME) 病態の一例.

    稲垣兼一, 大塚文男, 鈴木二郎, 三好智子, 大谷寛之, 三村由香里, 小倉俊郎, 槇野博史

    ホルモンと臨床   49   119 - 123   2008年

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  • IgG4関連疾患による視床下部・下垂体障害が疑われた一例.

    三好智子, 大塚文男, 塚本尚子, 鈴木二郎, 大谷寛之, 後藤順子, 小倉俊郎, 服部輝彦, 槇野博史

    日本内分泌学会雑誌   84   87 - 89   2008年

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  • 糖尿病性腎症.

    四方賢一, 槇野博史

    腎と透析   64   945 - 950   2008年

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  • 肉眼的血尿に引き続いて急性腎不全をきたした高齢男性.

    森永裕士, 杉山 斉, 槇野博史

    Medical Practice   25 ( 2 )   352 - 358   2008年

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  • World Diabetes Day・World Kidney Dayと病診連携の推進.

    槇野博史

    内科   101 ( 3 )   424   2008年

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  • 慢性腎臓病の診断とフォローアップ.内科シリーズ:ガイドライン.

    木野村賢, 杉山 斉, 槇野博史

    岡山医学会雑誌   120   83 - 86   2008年

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  • 慢性腎臓病の診断とフォローアップ.

    木野村賢, 杉山 斉, 槇野博史

    岡山医学会雑誌   120   83 - 86   2008年

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  • メタボリックシンドロームと慢性腎臓病の接点.

    寺見隆宏, 和田 淳, 槇野博史

    EBMジャーナル   9 ( 2 )   172 - 176   2008年

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  • Gastric diverticulum simulating left adrenal incidentaloma in a hypertensive patient

    Ryo Kodera, Fumio Otsuka, Kenicfii Inagaki, Tomoko Miyoshi, Toshio Ogura, Yasushi Tanimoto, Tetsuro Sei, Hirofumi Makino

    ENDOCRINE JOURNAL   54 ( 6 )   969 - 974   2007年12月

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    記述言語:英語   出版者・発行元:JAPAN ENDOCRINE SOC  

    A 46-year-old Japanese male with hypertension was referred for examination of left adrenal tumor incidentally detected by computed tomography (CT) scan. The patient had a 4-month history of hypertension. Abdominal CT demonstrated a low-density mass 2.5 cm in diameter in the left adrenal region that was observed as a high-intense lesion with T2-weighted magnetic resonance imaging. I-131-adosterol scintigraphy showed normal uptake of bilateral adrenals. The adrenocortical hormone levels were within normal ranges; however, urinary noradrenaline excretion was slightly elevated, likely due to concurrent sleep apnea syndrome. Based on the observation of a very tiny bubble in the ventral portion of the adrenal mass by careful review of CT images examined at a previous hospital, a restudy of abdominal CT with oral contrast was performed. In this restudy abdominal CT we observed positive enhancement of the left adrenal mass, indicating that the adrenal mass was a diverticulum derived from posterior gastric fornix. The present case study reinforces that preoperative differentiation from mimic adrenal tumors is necessary in cases of cystic adrenal mass in the left adrenal region.

    DOI: 10.1507/endocrj.K07E-025

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  • Modification of the Modification of Diet in Renal Disease (MDRD) Study equation for Japan

    Enyu Imai, Masaru Horio, Kosaku Nitta, Kunihiro Yamagata, Kunitoshi Iseki, Yusuke Tsukamoto, Sadayoshi Ito, Hirofumi Makino, Akira Hishida, Seiichi Matsuo

    AMERICAN JOURNAL OF KIDNEY DISEASES   50 ( 6 )   927 - 937   2007年12月

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    記述言語:英語   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

    Background: Glomerular filtration rate (GFR)-estimating equations based on serum creatinine level may not be accurate across racial groups because of differences among races in creatinine generation. The Modification of Diet in Renal Disease (MDRD) Study equation was developed in whites and African Americans, but performance was not evaluated in Japanese.
    Study Design: Diagnostic test accuracy. Cross-sectional retrospective study of 3 patient groups. Equation development in 2 groups (n = 247 in 2002 to 2004; n = 214 in 2003 to 2004 with measured GFR <90 mL/min/1.73 m(2)); external validation in a separate group (n = 153 from 1988 to 1994).
    Setting & Participants: Hospitalized Japanese patients with chronic kidney disease in 3 medical centers.
    Reference Test: Measured GFR (mGFR) computed from renal clearance of inulin.
    Index Test: Estimated GFR (eGFR) using the isotope dilution mass spectrometry (IDMS)-traceable 4-variable MDRD Study equation, a modified IDMS MDRD Study equation with a Japanese Society of Nephrology-Chronic Kidney Disease Initiatives (JSN-CKDI) coefficient derived in the development data set, and a new equation derived by refitting coefficients in the MDRD Study equation in the development data set.
    Measurements: Current creatinine assays were calibrated to standardized creatinine. Performance of equations was assessed as bias, accuracy, root-mean-squared error, and correlation coefficient of eGFR versus mGFR.
    Results: In the development data set, eGFR using the IDMS MDRD Study equation overestimated mGFR throughout the entire range. In the validation data set, the IDMS MDRD Study equation with the JSN-CKDI coefficient 0.741 and the new equation (JSN-CKDI) performed with significantly less bias and greater accuracy than the IDMS MDRD Study equation, but were similar to each other in accuracy and bias in patients with eGFR less than 60 mL/min/1.73 m(2). In the combined development and validation data sets, the JSN-CKDI coefficient was 0.763 (95% confidence interval, 0.743 to 0.783).
    Limitations: Possible drift in creatinine assays over time, possible lower creatinine generation in hospitalized patients, exclusion of patients with higher GFR from the development data set.
    Conclusion: GFR estimates using the IDMS MDRD Study equation with the JSN-CKDI coefficient or the new JSN-CKDI equation are more accurate than the IDMS MDRD Study equation in hospitalized Japanese patients with eGFR less than 60 mL/min/1.73 m(2). More studies are necessary to verify the accuracy of the JSN-CKDI coefficient and JSN-CKDI equation in other settings in Japan and elsewhere in Asia.

    DOI: 10.1053/j.ajkd.2007.09.004

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  • Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells

    Kazuyoshi Omori, Yasushi Shikata, Kei Sarai, Naomi Watanabe, Jun Wada, Noriko Goda, Noriyuki Kataoka, Kenichi Shikata, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY   293 ( 5 )   C1523 - C1531   2007年11月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Edaravone is a potent scavenger of hydroxyl radicals and is quite successful in patients with acute cerebral ischemia, and several organ-protective effects have been reported. Treatment of human microvascular endothelial cells with edaravone (1.5 mu M) resulted in the enhancement of transmonolayer electrical resistance coincident with cortical actin enhancement and redistribution of focal adhesion proteins and adherens junction proteins to the cell periphery. Edaravone also induced small GTPase Rac activation and focal adhesion kinase (FAK; Tyr(576)) phosphorylation associated with sphingosine-1-phosphate receptor type 1 (S1P(1)) transactivation. S1P(1) protein depletion by the short interfering RNA technique completely abolished edaravone-induced FAK ( Tyr576) phosphorylation and Rac activation. This is the first report of edaravone-induced endothelial barrier enhancement coincident with focal adhesion remodeling and cytoskeletal rearrangement associated with Rac activation via S1P(1) transactivation. Considering the well-established endothelial barrier-protective effect of S1P, endothelial barrier enhancement as a consequence of S1P(1) transactivation may at least partly be the potent mechanisms for the organ-protective effect of edaravone and is suggestive of edaravone as a therapeutic agent against systemic vascular barrier disorder.

    DOI: 10.1152/ajpcell.00524.2006

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  • Linkage between oxygen uptake at ventilatory threshold and muscle strength in subjects with and without metabolic syndrome

    Nobuyuki Miyatake, Takeshi Saito, Jun Wada, Hidetaka Nishikawa, Sumiko Matsumoto, Motohiko Miyachi, Masafumi Fujii, Hirofumi Makino, Takeyuki Numata

    ACTA MEDICA OKAYAMA   61 ( 5 )   255 - 259   2007年10月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We evaluated the linkage between oxygen uptake at the ventilatory threshold (VT) and muscle strength in subjects with and without metabolic syndrome. We used data of 226 Japanese men with metabolic syndrome and 265 Japanese men without the syndrome. Metabolic syndrome has recently been defined by a new criterion in Japan. Oxygen uptake at VT and muscle strength, i.e. grip strength and leg strength were measured. Oxygen uptake at VT and muscle strength/body weight were found to be significantly lower in subjects with metabolic syndrome than in those without the syndrome. However, the differences did not reach significant levels after adjusting for leg strength/body weight or oxygen uptake at VT. A combination of aerobic exercise and resistance training might be considered for preventing and improving metabolic syndrome.

    DOI: 10.18926/AMO/32895

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  • Comparison of ventilatory threshold and exercise habits between Japanese men with and without metabolic syndrome

    Nobuyuki Miyatake, Takeshi Saito, Jun Wada, Motohiko Miyachi, Izumi Tabata, Sumiko Matsumoto, Hidetaka Nishikawa, Hirofumi Makino, Takeyuki Numata

    DIABETES RESEARCH AND CLINICAL PRACTICE   77 ( 2 )   314 - 319   2007年8月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Objective: We compared the levels of ventilatory threshold (VT) and exercise habits in subjects with metabolic syndrome with those in age, sex-matched subjects without metabolic syndrome.
    Methods: We used data of 155 Japanese men (47.1 +/- 9.2 years) with metabolic syndrome; the diagnosis was given by the definition and the diagnostic standard for metabolic syndrome in Japan. The influence of metabolic syndrome on oxygen uptake, work rate and heart rate at VT, and exercise habits were evaluated.
    Results: Oxygen uptake and work rate at VT in subjects with metabolic syndrome were significantly lower than those in subjects without metabolic syndrome even after adjusting for body mass index (BMI). The number of subjects with exercise habits was significantly lower in metabolic syndrome. The subjects with exercise habits were significantly older than that in subjects without exercise habits. Furthermore, oxygen uptake and work rate at VT were significantly higher in subjects with exercise habits than those in subjects without exercise habits.
    Conclusion: Lower level of VT was characteristic in subjects with metabolic syndrome. Promotion of exercise habits is necessary for preventing and improving metabolic syndrome in Japanese men. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.diabres.2006.11.008

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  • Desmin as a marker of proteinuria in early stages of membranous nephropathy in elderly patients

    M. Maruyama, H. Sugiyama, K. Sada, M. Kobayashi, Y. Maeshima, Y. Yamasaki, H. Makino

    CLINICAL NEPHROLOGY   68 ( 2 )   73 - 80   2007年8月

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    記述言語:英語   出版者・発行元:DUSTRI-VERLAG DR KARL FEISTLE  

    Aims and method: Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults worldwide. Many patients with IMN are elderly, but little is known about the relationship regarding the morphological stage determined by electron microscopy (EM), the amount of proteinuria, and the expression of glomerular podocyte markers such as desmin and nephrin in nephrotic glomeruli in IMN. We studied 59 patients with histopathologically proven MTN. We compared the clinical features, EM stage classification, and the immunohistochemical features of glomerular expression of podocyte markers, including desmin and nephrin, between older (age ! 60 years) and younger (age < 60 years) patients. We also investigated these parameters in patients with minimal-change nephrotic syndrome (MCNS), minor glomerular abnormalities (MGA), and normal kidneys as agematched controls. Results: Prevalence of nephrotic syndrome was significantly higher in the older (52.9%) than the younger group (20.0%) of IMN. The level of proteinuria was higher in early stages (Stages I + II) than in late stages (Stages III + IV) in IMN. The glomerular expression of desmin in podocytes was significantly higher in IMN as compared to MCNS, MGA, or age-matched controls. Desmin expression was significantly increased in earlier EM stages (Stages I + 11) and in higher proteinuric group (daily proteinuria >= 1 g) of older patients with IMN. Reciprocally, the reduced expression of nephrin was associated with the early EM stages (Stages I + 11) of patients with IMN. Conclusions: We conclude that the expression of desmin in podocytes is upregulated in patients with IMN as compared to other glomerular diseases including MCNS or MGA, or to controls. In elderly patients with IMN, desmin expression was associated with early EM stages and heavy proteinuria, which may reflect phenotypic alteration of the podocyte nephrin, podocin, ZO-1, CD2AP, and so on [Mundel and Shankland 2002]. In diseased glomeruli, their expression and distribution is markedly altered from continuous distribution to discontinuous distribution along the glomerular capillary wall. However, the change in nephrin expression and its association with proteinuria in the immune complex-associated type of nephrotic syndrome such as IMN is poorly understood.
    Because few reports are available with pathological information on elderly patients with IN/lN, several clinical parameters were compared between elderly and younger ININ patients in this study. These parameters included daily proteinuria, morphological stages of EM in renal biopsy specimens and markers of podocyte injury, including desmin and nephrin.

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  • Effects of peroxisome proliferator-activated receptor activation on gonadotropin transcription and cell mitosis induced by bone morphogenetic proteins in mouse gonadotrope LβT2 cells.

    Takeda M, Otsuka.F, Otani H, Inagaki K, Miyoshi T, Suzuki J, Mimura Y, Ogura T, Makino H

    Journal of Endocrinology   194 ( 1 )   87 - 99   2007年7月

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  • Urinary PGDS levels are associated with vascular injury in type 2 diabetes patients

    Ritsuko Yoshikawa, Jun Wada, Kousuke Seiki, Takashi Matsuoka, Satoshi Miyamoto, Kenji Takahashi, Sachiko Ota, Kazuhi Taniai, Kazuyuki Hida, Minoru Yamakado, Kenichi Shikata, Yoshio Uehara, Yoshihiro Urade, Hirofumi Makino

    DIABETES RESEARCH AND CLINICAL PRACTICE   76 ( 3 )   358 - 367   2007年6月

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    記述言語:英語   出版者・発行元:ELSEVIER IRELAND LTD  

    Background: The presence of metabolic syndrome has been shown to be predictors of cardiovascular morbidity and mortality in patients with type 2 diabetes. In a cross-sectional clinical study, we investigated the association of metabolic syndrome with asymptomatic lacunar strokes and cardiovascular disease (CVD) and we compared its significance with urinary protein markers.
    Methods: We studied Japanese type 2 diabetes patients (n = 233, men = 124, women = 109). The diagnosis of metabolic syndrome was made according to WHO and International Diabetes Federation (IDF) criteria. Cardiovascular events were recorded and asymptomatic lacunar lesions were evaluated with magnetic resonance imaging (MRI). We also measured urinary levels of albumin, type IV collagen, beta 2-microglobulin (beta 2MG), N-acetyl-beta-D-glucosaminidase (NAG) and lipocalin-type prostaglandin D synthase (PGDS).
    Results: The prevalence of metabolic syndrome is 31.3% (IDF) and 52% (WHO) in 233 patients and microalbuminuria was present in 62 subjects (26.6%). Metabolic syndrome (WHO) significantly associated with asymptomatic lacunar lesions (p = 0.035, OR = 2.854, CI 1.075-7.579), while metabolic syndrome (IDF) or urinary markers failed to associate with presence of asymptomatic lacunar lesions. The presence of metabolic syndrome or microalbuminuria did not show significant association with CVD; however, the elevation of beta 2MG, NAG and PGDS showed significant association with CVD. By a logistic regression analysis using urinary proteins as independent variables, the presence of higher PGDS excretion independently associated with history of CVD (p = 0.025, OR= 3.847, CI 1.180-12.545).
    Conclusions: In type 2 diabetes patients, the elevation of urinary PGDS secretion closely associated with cardiovascular events and may be a supplemental or additional marker to the criteria of metabolic syndrome. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.diabres.2006.09.004

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  • Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient

    Enyu Imai, Masaru Horio, Kunitoshi Iseki, Kunihiro Yamagata, Tsuyoshi Watanabe, Shigeko Hara, Nobuyuki Ura, Yutaka Kiyohara, Hideki Hirakata, Toshiki Moriyama, Yasuhiro Ando, Kosaku Nitta, Daijo Inaguma, Ichiei Narita, Hiroyasu Iso, Kenji Wakai, Yoshinari Yasuda, Yusuke Tsukamoto, Sadayoshi Ito, Hirofumi Makino, Akira Hishida, Seiichi Matsuo

    Clinical and Experimental Nephrology   11 ( 2 )   156 - 163   2007年6月

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    記述言語:英語  

    Background. The number of patients with end-stage renal disease (ESRD) in Japan has continuously increased in the past three decades. In 2005, 36 063 patients whose average age was 66 years entered a new dialysis program. This large number of ESRD patients could be just the tip of the iceberg of an increasing number of patients with chronic kidney disease (CKD). However, to date, a nationwide epidemiological study has not been conducted yet to survey the CKD population. Methods. Data for 527 594 (male, 211 034
    female, 316 560) participants were obtained from the general adult population aged over 20 years who received annual health check programs in 2000-2004, from seven different prefectures in Japan: Hokkaido, Fukushima, Ibaraki, Tokyo, Osaka, Fukuoka, and Okinawa prefectures. The glomerular filtration rate (GFR) for each participant was estimated from the serum creatinine values, using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation modified by the Japanese coefficient. Results. The prevalences of CKD stage 3 in the study population, stratified by age groups of 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80-89 years, were 1.4%, 3.6%, 10.8%, 15.9%, 31.8%, 44.0%, and 59.1%, respectively, predicting 19.1 million patients with stage 3 CKD in the Japanese general adult population of 103.2 million in 2004. CKD stage 4 + 5 was predicted in 200 000 patients in the Japanese general adult population. Comorbidity of hypertension, diabetes, and proteinuria increased as the estimated GFR (eGFR) decreased. The prevalence of concurrent CKD was significantly higher in hypertensive and diabetic populations than in the study population overall when CKD was defined as being present with an eGFR of less than 40 ml/min per 1.73 m2 instead of less than 60 ml/min per 1.73 m2. Conclusions. About 20% of the Japanese adult population (i.e., approximately 19 million people) are predicted to have stage 3 to 5 CKD, as defined by a GFR of less than 60 ml/min per 1.73 m2. © 2007 Japanese Society of Nephrology.

    DOI: 10.1007/s10157-007-0463-x

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  • An elderly patient with sarcoidosis manifesting panhypopituitarism with central diabetes insipidus

    Tomoko Miyoshi, Fumio Otsuka, Masaya Takeda, Kenichi Inagaki, Hiroyuki Otani, Toshio Ogura, Ken Ichiki, Tetsuki Amano, Hirofumi Makino

    ENDOCRINE JOURNAL   54 ( 3 )   425 - 430   2007年6月

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    記述言語:英語   出版者・発行元:JAPAN ENDOCRINE SOC  

    We here report a 77-year-old Japanese male who suffered general fatigue with progressive thirst and polyuria. Central diabetes insipidus was diagnosed by depletion of vasopressin secretion in response to increases ill Serum osmolality. Secretory responses of anterior pituitary hormones including adrenocorticotropin, thyrotropin, gonadotropins and growth hormone were severely impaired. Diffuse swelling of the infundibulum as well as lack of T1-hyperintense signal in the posterior lobe was noted by pituitary magnetic resonance imaging. The presence of bilateral hilar lymphadenopathy and increased CD4/CD8 ratio in bronchoalveolar lavage fluid was diagnostic for lung sarcoidosis. Physiological doses of corticosteroid and thyroid hormone were administered ill addition to desmopressin Supplementation. Complete regression of the neurohypophysial swelling was notable two years after corticosteroid replacement. Diffuse damage of anterior pituitary combined with hypothalamic involvement leading to central diabetes insipidus is a rare manifestation in such elderly patients with neurosarcoidosis.

    DOI: 10.1507/endocrj.K06-161

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  • Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes

    Hirofumi Makino, Masakazu Haneda, Tetsuya Babazono, Tatsumi Moriya, Sadayoshi Ito, Yasuhiko Iwamoto, Ryuzo Kawamori, Masahiro Takeuchi, Shigehiro Katayama

    DIABETES CARE   30 ( 6 )   1577 - 1578   2007年6月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    DOI: 10.2337/dc06-1998

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  • The Role for HNF-1 beta-Targeted Collectrin in Maintenance of Primary Cilia and Cell Polarity in Collecting Duct Cells

    Yanling Zhang, Jun Wada, Akihiro Yasuhara, Izumi Iseda, Jun Eguchi, Kenji Fukui, Qin Yang, Kazuya Yamagata, Thomas Hiesberger, Peter Igarashi, Hong Zhang, Haiyan Wang, Shigeru Akagi, Yashpal S. Kanwar, Hirofumi Makino

    PLOS ONE   2 ( 5 )   e414   2007年5月

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    記述言語:英語   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1 alpha, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1 beta and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to gamma-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1 beta and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1 beta regulated genes.

    DOI: 10.1371/journal.pone.0000414

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  • TNF-α inhibits BMP-induced osteoblast differentiation through activating SAPK/JNK signaling.

    Mukai T, Otsuka F, Otani H, Yamashita M, Koji T, Inagaki K, Yamamura M, Makino H

    Biochemical and Biophysical Research Communications   356 ( 4 )   1004 - 1010   2007年5月

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  • Antagonistic effects of bone morphogenetic protein-4 and-7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation

    Hiroyuki Otani, Fumio Otsuka, Kenichi Inagaki, Masaya Takeda, Tomoko Miyoshi, Jiro Suzuki, Tomoyuki Mukai, Toshio Ogura, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY   292 ( 5 )   F1513 - F1525   2007年5月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Aldosterone and angiotensin II (ANG II) contribute to the development and progression of renal damage. Here we investigated the effects of bone morphogenetic proteins (BMPs) on renal cell proliferation evoked by aldosterone and ANG II with mouse mesangial cells, which express mineralocorticoid receptors (MR), ANG II type 1 receptors, and BMP signaling molecules. Aldosterone and ANG II stimulated mesangial cell mitosis and activated ERK1/2 and SAPK/JNK signaling. These aldosterone effects were neutralized by the MR antagonist eplerenone and inhibition of transcription or translation, suggesting the involvement of genomic activation via MR. BMP-4 and BMP-7 stimulated Smad1, -5, -8 signaling more potently than BMP-2 and BMP-6, leading to suppression of mesangial cell mitosis and MR expression. MAPK inhibitors including U-0126 and SP-600125, but not SB-203580, suppressed aldosterone-induced cellular DNA synthesis, implying that ERK1/2 and SAPK/JNK pathways play crucial roles in mesangial cell proliferation. BMP-4 and BMP-7 inhibited phosphorylation of ERK1/2 and SAPK/JNK induced by aldosterone while activating p38 pathway, resulting in inhibition of aldosterone-induced cell mitosis. In contrast, aldosterone modulated the mesangial BMP system by decreasing expression of ALK-3, BMP-4, and BMP-7 while increasing inhibitory Smad6 expression. Thus novel functional cross talk between the mesangial BMP system and aldosterone signaling was uncovered, in which inhibition of MAPK signaling and MR expression by BMP-4 and BMP-7 may be involved in ameliorating renal damage due to mesangial proliferation caused by aldosterone.

    DOI: 10.1152/ajprenal.00402.2006

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  • Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappa B activation

    Sakiko Ohga, Kenichi Shikata, Kosuke Yozai, Shinichi Okada, Daisuke Ogawa, Hitomi Usui, Jun Wada, Yasushi Shikata, Hirofumi Makino

    AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY   292 ( 4 )   F1141 - F1150   2007年4月

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    記述言語:英語   出版者・発行元:AMER PHYSIOLOGICAL SOC  

    Thiazolidinedione (TZD), a ligand for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), exerts anti-inflammatory effects independently of the insulin-sensitizing effect. In the present study, we tested the hypothesis that TZD prevents the progression of diabetic nephropathy by modulating the inflammatory process. Five-week-old Sprague-Dawley rats were divided into three groups: 1) nondiabetic control rats (non-DM), 2) diabetic rats (DM), and 3) diabetic rats treated with pioglitazone (DM + pio). Diabetes was induced by injection with streptozotocin (STZ). The DM + pio group received 0.0002% pioglitazone mixed in chow for 8 wk after induction of diabetes. Blood glucose and HbA1c were elevated in diabetic rats but did not change by treatment with pioglitazone. Pioglitazone reduced urinary albumin excretion and glomerular hypertrophy, suppressed the expression of transforming growth factor (TGF)-beta, type IV collagen, and ICAM-1, and infiltration of macrophages in the kidneys of diabetic rats. Furthermore, renal NF-kappa B activity was increased in diabetic rats and reduced by pioglitazone. PPAR-gamma was expressed in glomerular endothelial cells in the diabetic kidney and in cultured glomerular endothelial cells. High-glucose conditions increased the expression of ICAM-1 and the activation of NF-kappa B in cultured glomerular endothelial cells. These changes were reduced by pioglitazone, ciglitazone, and pyrrolidine dithiocarbamate, an inhibitor of NF-kappa B. However, pioglitazone did not show the changes in the presence of PPAR-kappa B antagonist GW9662. Our results suggest that the preventive effects of pioglitazone may be mediated by its anti-inflammatory actions, including inhibition of NF-kappa B activation, ICAM-1 expression, and macrophage infiltration in the diabetic kidney.

    DOI: 10.1152/ajprenal.00288.2005

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  • Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion

    Jiro Suzuki, Fumio Otsuka, Kenichi Inagaki, Hiroyuki Otani, Tomoko Miyoshi, Tomohiro Terasaka, Toshio Ogura, Masako Omori, Yasutomo Nasu, Hirofumi Makino

    HYPERTENSION RESEARCH   30 ( 4 )   367 - 373   2007年4月

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    記述言語:英語   出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE  

    A 35-year-old Japanese woman was referred for further examination of persistent hypertension with hypokalemia. Her serum aldosterone levels were high and her plasma renin activity markedly suppressed. Radiological examinations revealed the presence of a 3-cm diameter left adrenal tumor. I-131-adosterol was specifically accumulated in the left adrenal tumor, whereas the accumulation in the right adrenal was completely suppressed. Low-dose dexamethasone failed to suppress cortisol secretion although the serum cortisol levels were within the normal range. Urinary excretion of 17-hydroxycorticosteroids but not 17-ketosteroids was increased. Levels of plasma adrenocorticotropin (ACTH) and serum dehydroepiandrosterone sulfate (DHEAS) were decreased. Upon diagnosis of left aldosteronoma with autonomous secretion of cortisol, left adrenalectomy was performed by laparoscopy. In the resected adenoma tissues, clear cells expressed P450c17 protein and the ratio of CYP17/CYP11B2 mRNA evaluated by quantitative real-time polymerase chain reaction (PCR) was apparently higher than that of typical aldosteronomas. Based on the corticotropin-releasing hormone (CRH) loading tests, the contra-lateral adrenal functions were restored 3 months after surgery. These results indicate that evaluation for autonomy of cortisol secretion and contralateral adrenal function is clinically important to avoid the risk of adrenal failure after surgery for primary aldosteronism.

    DOI: 10.1291/hypres.30.367

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  • The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis

    Masako Tabuchi, Katsumi Inoue, Hitomi Usui-Kataoka, Kazuko Kobayashi, Misako Teramoto, Koji Takasugi, Kenichi Shikata, Masahiro Yamamura, Kenji Ando, Keiichiro Nishida, Junko Kasahara, Noriaki Kume, Luis R. Lopez, Kazuaki Mitsudo, Masakiyo Nobuyoshi, Tatsuji Yasuda, Toru Kita, Hirofumi Makino, Eiji Matsuura

    JOURNAL OF LIPID RESEARCH   48 ( 4 )   768 - 781   2007年4月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    C-reactive protein (CRP) is one of the strongest independent predictors of cardiovascular disease. We have previously reported that oxidized LDL (oxLDL) interacts with beta 2-glycoprotein I (beta 2GPI), implicating oxLDL/P2GPI complexes as putative autoantigens in autoimmune-mediated atherosclerotic vascular disease. In this study, we investigated the interaction of CRP with oxLDL/beta 2GPI complexes and its association with atherosclerosis in patients with diabetes mellitus (DM). CRP/oxLDL/R2GPI complexes were predominantly found in sera of DM patients with atherosclerosis. In contrast, noncomplexed CRP isoforms were present in sera of patients with acute/chronic inflammation, i.e., various pyrogenic diseases, rheumatoid arthritis (RA), and DM. Immunohistochemistry staining colocalized CRP and beta 2GPI together with oxLDL in carotid artery plaques but not in synovial tissue from RA patients, strongly suggesting that complex formation occurs during the development of adierosclerosis. Serum levels of CRP correlated with soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and oxLDL/beta 2GPI complexes correlated with total cholesterol and hemoglobin Al c. Thus, the generation of CRP/oxLDL/beta 2GPI complexes seems to be associated with arterial inflammation, hyperglycemia, and hypercholesterolemia. CRP/oxLDL/R2GPI complexes can be distinguished from pyrogenic noncomplexed CRP isoforms and may represent a more specific and predictive marker for atherosclerosis.

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  • Recruitment of CD16(+) monocytes into synovial tissues is mediated by fractalkine and CX3CR1 in rheumatoid arthritis patients

    Ryusuke Yano, Masahiro Yamamura, Katsue Sunahori, Kouji Takasugi, Jiro Yamana, Masanori Kawashima, Hirofumi Makino

    ACTA MEDICA OKAYAMA   61 ( 2 )   89 - 98   2007年4月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    CD16(+) monocytes, identified as a minor population of monocytes in human peripheral blood, have been implicated in several inflammatory diseases, including rheumatoid arthritis (RA). Fractalkine (FKN, CX3CL1), a member of the CX3 C subfamily, is induced by pro-inflammatory cytokines, while a receptor for FKN, CX3CRI, is capable of mediating both leukocyte migration and firm adhesion. Here, we investigated the role of FKN and CX3CRI in activation of CD16(+) monocytes and their recruitment into synovial tissues in RA patients. High levels of soluble FKN were detected in the synovial fluid and sera of RA patients. Circulating CD16(+) monocytes showed a higher level of CX3CRI expression than CD16(-) monocytes in both RA patients and healthy subjects. High level expression of CX3CRI was also seen in CD16(+) monocytes localized to the lining layer in RA synovial tissue. In the in vitro culture experiments, IL-10 induced CX3CRI expression on the surface of monocytes, and TNF proportional to induced membrane-bound FKN as well as soluble FKN expression in synovial fibroblasts. Moreover, soluble FKN was capable of inducing IL-1/beta and IL-6 by activated monocytes. These results suggest that FKN might preferentially mediate migration and recruitment of CD16(+) monocytes, and might contribute to synovial tissue inflammation.

    DOI: 10.18926/AMO/32882

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  • Changes of gene expression profiles in macrophages stimulated by angiotensin II - Angiotensin II induces MCP-2 through AT(1)-receptor

    Atsuhito Tone, Kenichi Shikata, Daisuke Ogawa, Sakiko Sasaki, Ryo Nagase, Motofumi Sasaki, Kosuke Yozai, Hitomi Kataoka Usui, Shinichi Okada, Jun Wada, Yasushi Shikata, Hirofumi Makino

    JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM   8 ( 1 )   45 - 50   2007年3月

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    記述言語:英語   出版者・発行元:SAGE PUBLICATIONS LTD  

    Introduction. Macrophages play critical roles in the development of atherosclerosis and diabetic nephropathy as well as many inflammatory diseases. Angiotensin II type 1 receptor antagonists (AIIA) are beneficial for the prevention of atherosclerosis and diabetic nephropathy suggesting that angiotensin II (Ang II) promotes the development of these diseases. it has recently been reported that Ang II exerts proinflammatory actions in vivo and in vitro. This study was aimed to clarify the direct effects of Ang II on monocytes/macrophages.
    Materials and methods. PMA-treatedTHP-1 cells, a human monocytic leukaemia cell line, were treated with Ang II (10(-6) mol/L) for 24 hours with or without AIIA (CV11974). We evaluated gene expression profiles of these cells using DNA microarray system and quantified them by real-time RT-PCR.
    Results. DNA microarray revealed that in total 19 genes, including monocyte chemoattractant protein (MCP)-2, were up-regulated by Ang II and down-regulated by AIIA. Real-time RT-PCR showed that up-regulation of MCP-2 with Ang II is blocked by the ARA (CV11974) but not by an AT(2)-receptor antagonist.
    Conclusions. These results suggest that Ang II directly stimulates MCP-2 expression through AT(1)-receptors in activated macrophages. Ang II may contribute to the persistence or amplification of microinflammation in vessel walls, heart and kidney. Vasculoprotective or renoprotective effects of ARA might partly depend on direct anti-inflammatory effects on macrophages.

    DOI: 10.3317/jraas.2007.007

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  • Enhanced TGF-β/Smad signaling in the early stage of diabetic nephropathy is independent of the AT1a receptor.

    Okazaki Y, Yamasaki Y, Uchida H, Okamoto K, Satoh M, Maruyama K, Maesima Y, Sugiyama H, Sugaya T, Kashihara N, Makino H

    Clin Exp Nephrol   11 ( 1 )   77 - 87   2007年3月

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  • Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease

    Enyu Imai, Masaru Horio, Kosaku Nitta, Kunihiro Yamagata, Kunitoshi Iseki, Shigeko Hara, Nobuyuki Ura, Yutaka Kiyohara, Hideki Hirakata, Tsuyoshi Watanabe, Toshiki Moriyama, Yasuhiro Ando, Daiki Inaguma, Ichiei Narita, Hiroyasu Iso, Kenji Wakai, Yoshinari Yasuda, Yusuke Tsukamoto, Sadayoshi Ito, Hirofumi Makino, Akira Hishida, Seiichi Matsuo

    Clinical and Experimental Nephrology   11 ( 1 )   41 - 50   2007年3月

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    記述言語:英語  

    Background. Accurate estimation of the glomerular filtration rate (GFR) is crucial for the detection of chronic kidney disease (CKD). In clinical practice, GFR is estimated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) study equation or the Cockcroft-Gault (CG) equation instead of the time-consuming method of measured clearance for exogenous markers such as inulin. In the present study, the equations originally developed for a Caucasian population were tested in Japanese CKD patients, and modified with the Japanese coefficient determined by the data. Methods. The abbreviated MDRD study and CG equations were tested in 248 Japanese CKD patients and compared with measured inulin clearance (Cin) and estimated GFR (eGFR). The Japanese coefficient was determined by minimizing the sum of squared errors between eGFR and Cin. Serum creatinine values of the enzyme method in the present study were calibrated to values of the noncompensated Jaffé method by adding 0.207 mg/dl, because the original MDRD study equation was determined by the data for serum creatinine values measured by the noncompensated Jaffé method. The abbreviated MDRD study equation modified with the Japanese coefficient was validated in another set of 269 CKD patients. Results. There was a significant discrepancy between measured Cin and eGFR by the 1.0 x MDRD or CG equations. The MDRD study equation modified with the Japanese coefficient (0.881 x MDRD) determined for Japanese CKD patients yielded lower mean difference and higher accuracy for GFR estimation. In particular, in Cin 30-59 ml/min per 1.73 m2, the mean difference was significantly smaller with the 0.881 x MDRD equation than that with the 1.0 x MDRD study equation (1.9 vs 7.9 ml/min per 1.73 m2
    P &lt
    0.01), and the accuracy was significantly higher, with 60% vs 39% of the points deviating within 15%, and 97% vs 87% of points within 50%, respectively (both P &lt
    0.01). Validation with the different data set showed the correlation between eGFR and Cin was better with the 0.881 x MDRD equation than with the 1.0 x MDRD study equation. In Cin less than 60 ml/min per 1.73 m 2, the accuracy was significantly higher, with 85% vs 69% of the points deviating within 50% (P &lt
    0.01), respectively. The mean difference was also significantly smaller (P &lt
    0.01). However, GFR values calculated by the 0.881 × MDRD equation were still underestimated in the range of Cin over 60 ml/min per 1.73 m2. Conclusions. Although the Japanese coefficient improves the accuracy of GFR estimation of the original MDRD study equation, a new equation is needed for more accurate estimation of GFR in Japanese patients with CKD stages 3 and 4. © 2007 Japanese Society of Nephrology.

    DOI: 10.1007/s10157-006-0453-4

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  • Endostatin peptide, an inhibitor of angiogenesis, prevents the progression of peritoneal sclerosis in a mouse experimental model

    K. Tanabe, Y. Maeshima, K. Ichinose, H. Kitayama, Y. Takazawa, K. Hirokoshi, M. Kinomura, H. Sugiyama, H. Makino

    KIDNEY INTERNATIONAL   71 ( 3 )   227 - 238   2007年2月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Peritoneal sclerosis is a major and serious complication in patients on long-term continuous ambulatory peritoneal dialysis ( PD). The involvement of angiogenesis and proangiogenic factors such as vascular endothelial growth factor ( VEGF)-A in progressing peritoneal sclerosis has been reported. We previously reported the therapeutic efficacy of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in a mouse diabetic nephropathy model. Here, we examined the therapeutic effect of endostatin peptide in preventing progression in a mouse peritoneal sclerosis model. Male ICR mice received intraperitoneal injections of chlorhexidine gluconate ( CG) every other day to induce peritoneal sclerosis. Endostatin peptide ( 1 or 4mg/kg/day) was administered via subcutaneously implanted osmotic minipumps. Peritoneal sclerosis ( day 24) was significantly suppressed by endostatin peptide in a dose-dependent manner. Peritoneal accumulation of type III collagen was significantly suppressed by endostatin peptide. Increase in the number of CD31( +) blood vessels, F4/80( +) monocyte/macrophage accumulation, and 5-bromodeoxyuridine(+) proliferating cells was significantly inhibited by endostatin peptide. Increase in peritoneal expression of VEGF-A, profibrotic transforming growth factor-beta 1, and alpha-smooth muscle actin was suppressed by endostatin peptide. Immunoreactivity for endogenous endostatin ( whole molecule) and endostatin receptor alpha 5 beta 1-integrin was increased and colocalized to CD31( +) blood vessels in the thickened peritonea of CG-injected mice. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in preventing peritoneal sclerosis, a severe complication in patients undergoing long-term PD.

    DOI: 10.1038/sj.ki.5002040

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  • Regulatory expression of bone morphogenetic protein-6 system in aldosterone production by human adrenocortical cells

    Kenichi Inagaki, Fumio Otsuka, Jiro Suzuki, Hiroyuki Otani, Masaya Takeda, Yoshihiro Kano, Tomoko Miyoshi, Misuzu Yamashita, Toshio Ogura, Hirofumi Makino

    REGULATORY PEPTIDES   138 ( 2-3 )   133 - 140   2007年2月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    Bone morphogenetic protein-6 (BMP-6) enhances aldosterone production by upregulating angiotensin II (Ang II)-to-MAPK pathway. Here we investigated effects of Ang II and potassium on the BMP system in human adrenocortical H295R cells. BMP-6 transcription was transiently downregulated by treatments with Ang II and potassium. Aldosterone also decreased BMP-6 expression at a high concentration. Chemical inhibitions of transcription and translation abolished the transient reduction of BMP-6, suggesting that destabilization of BMP-6 mRNA was hardly involved while new protein synthesis was possibly mediated in this mechanism. However, BMP-6 protein was stably detected during the exposures of AngII and potassium. Notably, Ang II, potassium and aldosterone decreased mRNA levels of follistatin that extracellularly neutralizes bioactivities of activins and BMPs although the BMP-6 receptor expression was unaffected. Given the maintenance of bioavailable BMP-6 protein and the receptor expression in adrenocortical cells, endogenous BMP-6 may be a key autocrine modulator for aldosterone production. (c) 2006 Elsevier B.V All rights reserved.

    DOI: 10.1016/j.regpep.2006.08.014

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  • Macrophage scavenger receptor-A-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation

    Hitorni Kataoka Usui, Kenichi Shikata, Motofurni Sasaki, Shinichi Okada, Mitsuhiro Matsuda, Yasushi Shikata, Daisuke Ogawa, Yuichi Kido, Ryo Nagase, Kosuke Yozai, Sakiko Ohga, Atsuhito Tone, Jun Wada, Masahiro Takeya, Seikoh Horiuchi, Tatsuhiko Kodama, Hirofunti Makino

    DIABETES   56 ( 2 )   363 - 372   2007年2月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    Microinflammation is a common major mechanism in the pathogenesis of diabetic vascular complications, including diabetic nephropathy. Macrophage scavenger receptor-A (SR-A) is a multifunctional receptor expressed on macrophages. This study aimed to determine the role of SR-A in diabetic nephropathy using SR-A-deficient (SR-A(-/-)) mice. Diabetes was induced in SR-A(-/-) and wild-type (SRA(+/+)) mice by streptozotocin injection. Diabetic SR-A(+/+) mice presented characteristic features of diabetic nephropathy: albuminuria, glomerular hypertrophy, mesangial matrix expansion, and overexpression of transforming growth factor-P at 6 months after induction of diabetes. These changes were markedly diminished in diabetic SR-A(-/-) mice, without differences in blood glucose and blood pressure levels. Interestingly, macrophage infiltration in the kidneys was dramatically decreased in diabetic SR-A(-/-) mice compared with diabetic SR-A(+/+) mice. DNA microarray revealed that proinflammatory genes were overexpressed in renal cortex of diabetic SR-A(+/+) mice and suppressed in diabetic SR-A(-/-) mice. Moreover, anti-SR-A antibody blocked the attachment of monocytes to type IV collagen substratum but not to endothelial cells. Our results suggest that SR-A promotes macrophage migration into diabetic kidneys by accelerating the attachment to renal extracellular matrices. SR-A may be a key molecule for the inflammatory process in pathogenesis of diabetic nephropathy and a novel therapeutic target for diabetic vascular complications.

    DOI: 10.2337/db06-0359

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  • Comparison of hepatic enzymes between Japanese men with and without metabolic syndrome

    Nobuyuki Miyatake, Sumiko Matsumoto, Hirofumi Makino, Takeyuki Numata

    ACTA MEDICA OKAYAMA   61 ( 1 )   31 - 34   2007年2月

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    記述言語:英語   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    We compared the levels of hepatic enzymes in 220 Japanese men with metabolic syndrome with those in age and sex-matched subjects without the syndrome. Metabolic syndrome was defined by the new criteria published in Japan, and hepatic enzymes, i.e., aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (gamma GTP), were measured. AST, ALT and gamma GTP in subjects with metabolic syndrome were significantly higher than those in subjects without the syndrome, and metabolic syndrome was closely associated with hepatic enzymes in this cohort of Japanese men.

    DOI: 10.18926/AMO/32912

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  • Differential regulation of steroidogenesis by bone morphogenetic proteins in granulosa cells: Involvement of extracellularly regulated kinase signaling and oocyte actions in follicle-stimulating hormone-induced estrogen production

    Tomoko Miyoshi, Fumio Otsuka, Kenichi Inagaki, Hiroyuki Otani, Masaya Takeda, Jiro Suzuki, Junko Goto, Toshio Ogura, Hirofumi Makino

    ENDOCRINOLOGY   148 ( 1 )   337 - 345   2007年1月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    In the present study, we investigated the cellular mechanism by which oocytes and bone morphogenetic proteins (BMPs) govern FSH-induced steroidogenesis using rat primary granulosa cells. BMP-6 and BMP-7 both inhibited FSH- and forskolin (FSK)-induced progesterone synthesis and reduced cAMP synthesis independent of the presence or absence of oocytes. BMP-7 also increased FSH-induced estradiol production, and the response was further augmented in the presence of oocytes. In contrast, BMP-6 had no impact on estradiol synthesis regardless of the presence of oocytes. Because BMP-7 changed neither FSK- nor cAMP-induced estradiol production, the BMP-7 action was mediated through a FSH receptor signaling mechanism that was independent of cAMP-protein kinase A pathway. Treatment with FSH but not cAMP activated ERK1/2 phosphorylation in granulosa cells, which was further accelerated by oocytes. A specific ERK inhibitor, U0126, increased estradiol production and decreased FSH- and FSK-induced progesterone production and cAMP synthesis. This suggests that ERK activation is directly linked to inhibition of estradiol synthesis and amplification of cAMP. Moreover, FSH- induced ERK1/2 phosphorylation was inhibited by BMP-7 but not influenced by BMP-6. In contrast, BMP signaling including Smad1/5/8 phosphorylation and Id-1 transcription was up-regulated by FSH and oocytes in granulosa cells through inhibition of Smad6/7 expression. Collectively, oocytes enhance FSH- induced MAPK activation and BMP signaling in granulosa cells, which leads to differential regulation of steroidogenesis elicited by BMPs in the presence of FSH in developing follicles.

    DOI: 10.1210/en.2006-0966

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  • Apparent mineralocorticold excess manifested in an elderly patient with hypothyroidism

    Kenichi Inagaki, Fumio Otsuka, Hiroyuki Otani, Chikage Sato, Tomoko Miyoshi, Toshio Ogura, Hirofumi Makino

    AMERICAN JOURNAL OF HYPERTENSION   20 ( 1 )   104 - 107   2007年1月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

    The syndrome of apparent mineralocorticoid excess (AME) is characterized by persistent hypertension and hypokalemia, which is caused by impaired inactivation of cortisol (F) to cortisone (E). The thyroid hormone has been known to influence the F to E conversion leading to efficacious inactivation of F into E. However, there have been no reports regarding the clinical manifestation of secondary AME due to hypothyroidism. Here we report an elderly patient who manifested AME, showing persistent hypertension with hypokalemia induced by primary hypothyroidism. Maintenance of euthyroid conditions ameliorated the concurrent AME and restored adrenal secretion of aldosterone after the recovery of the F to E shuttle. This case report would broaden our clinical recognition regarding acquired AME in relation to thyroid dysfunction.

    DOI: 10.1016/j.amjhyper.2006.06.012

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  • 腎保護作用のエビデンスー糖尿病性腎症を中心にー

    中司敦子, 和田 淳, 槇野博史

    日医雑誌   136 ( 6 )   2007年

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  • 第51回日本透析医学会ワークショップより「CAPD療法の新しい戦略―残存腎機能維持を考えるー」

    槇野博史, 中本雅彦

    透析会誌   40 ( 6 )   463   2007年

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  • 特集 糖尿病腎症発症と適正管理 血管新生抑制因子による糖尿病腎症進展制御

    前島洋平, 一瀬邦弘, 槇野博史

    内分泌・糖尿病科   24 ( 6 )   552 - 560   2007年

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  • 糖尿病特集 糖尿病性腎症の予防と治療―早期には血糖、進行期には血圧に比重を置いた治療を推奨

    羽田勝計, 槇野博史

    Medical Tribune   ( 2007.8.16 )   65 - 68   2007年

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  • <国内外のCKDに対するエビデンス> 糖尿病性腎症 -日本の研究からー

    四方賢一, 槇野博史

    内科   100 ( 1 )   2007年

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  • 日本慢性腎臓病対策協議会―CKDの国民的な取り組みー

    槇野博史

    メディカル・ビューポイント(MVP)   28 ( 9 )   2007年

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  • 慢性腎臓病(CKD)―治療とケアー 日本におけるCKD対策

    井上達之, 杉山 斉, 槇野博史

    臨床看護   33 ( 9 )   1274 - 1281   2007年

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  • ループス腎炎の動向と今後の治療戦略の考え方

    高沢有紀, 佐田憲映, 槇野博史

    Modern Phusician   27 ( 3 )   2007年

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  • 注意すべきCKD:糖尿病性腎症

    宮本 聡, 四方賢一, 槇野博史

    医学のあゆみ   222 ( 10 )   2007年

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  • ループス腎炎の新分類に基づいた治療戦略

    槇野博史, 小林みずほ, 佐田憲映

    日本内科学会雑誌   96 ( 9 )   2007年

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  • SLEと動脈硬化

    佐田憲映, 槇野博史

    リウマチ科   38 ( 2 )   195 - 198   2007年

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  • 腎疾患の病態生理:急性腎不全編 2.急性腎不全に伴う障害尿細管の修復

    木野村 賢, 前島洋平, 喜多村真治, 槇野博史

    腎と透析   63 ( 4 )   448 - 452   2007年

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  • INNOVATION特集 RASの新発見―臨床編―

    槇野博史

    Angiotensin Reserarch   4 ( 3 )   2007年

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  • 生涯教育シリーズ73 腎。泌尿器疾患診療マニュアル 小児から成人まで

    片岡仁美, 槇野博史

    日本医師会雑誌   136 ( 特別号2 )   204 - 207   2007年

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  • ループス腎炎新分類に基づく治療戦略

    槇野博史

    日本内科学会雑誌   96   90   2007年

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  • 糖尿病性微小血管障害におけるedaravoneの血管内皮保護作用についての検討

    更井 啓, 四方泰史, 大森一慶, 渡辺直美, 和田 淳, 四方賢一, 槇野博史

    Phrma Medica   25 ( 6 )   2007年

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  • わが国における糖尿病性腎症の研究の歴史と今後の展望

    槇野博史

    日本腎臓学会会誌   49 ( 6 )   529 - 754   2007年

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  • 特集:生活習慣と腎 メタボリック症候群からみた腎臓

    寺見隆宏, 和田 淳, 槇野博史

    腎臓   30 ( 2 )   104 - 110   2007年

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  • 糖尿病透析患者の血糖コントロール

    福岡晃輔, 中尾一志, 槇野博史

    腎と透析   63 ( 5 )   649 - 654   2007年

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  • 腎障害

    神崎資子, 和田 淳, 槇野博史

    日本医師会雑誌   136   S146-S148   2007年

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  • <診療controversy> ループス腎炎に対する免疫抑制療法 -慎重な立場から-

    田邊克幸, 佐田憲映, 槇野博史

    内科   99 ( 4 )   697 - 700   2007年

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  • 利尿薬の最新知識と使い方 腎不全に対する利尿薬の使い方

    森本尚孝, 中尾一志, 槇野博史

    成人病と生活習慣病   37 ( 8 )   923 - 927   2007年

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  • 慢性腎臓病の重要性

    菊本陽子, 杉山 斉, 槇野博史

    成人病と生活習慣病   37   21 - 24   2007年

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  • メタボリック症候群からみた腎臓

    寺見隆宏, 和田 淳, 槇野博史

    腎臓   30 ( 2 )   104 - 110   2007年

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  • 糖尿病性腎症

    西下伸吾, 四方賢一, 槇野博史

    からだの科学   255   2007年

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  • Gastric Diverticulum Simulating Left Adrenal Incidentaloma in a Hypertensive Patient.

    Kodera R, Otsuka F, Inagaki K, Miyoshi T, Ogura T, Tanimoto Y, Sei T, Makino H

    Endocrine Journal   56   969 - 974   2007年

  • ふせごう 静かに進む慢性腎炎 8月27日 危険信号を見逃さない 8月28日 悪化させない食事と薬 8月29日 透析と上手につきあう

    槇野博史

    NHKテレビテキスト きょうの健康   ( 8 )   2007年

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  • 危険因子:微量アルブミン尿

    村上和敏, 和田 淳, 槇野博史

    動脈硬化予防   6 ( 1 )   86 - 88   2007年

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  • メタボリックシンドローム研究の進展 メタボリックシンドロームと微量アルブミン尿

    村上和敏, 和田 淳, 槇野博史

    内分泌・糖尿病科   24 ( 5 )   467 - 472   2007年

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  • 脂質代謝異常―高脂血症・低脂血症- Ⅵ.脂質代謝異常の臨床 低脂血症 各病態における二次性低脂血症の発生機序とその治療

    勅使川原早苗, 和田 淳, 槇野博史

    日本臨牀   65 ( 7 )   2007年

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  • 世界遺産の病院

    槇野博史

    OKAYAMA UNIVERSITY HOSPITAL Monthly Letter   ( 8 )   2007年

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  • 県民フォーラム「腎臓病を考える」STOP the 慢性腎臓病!―早期発見とその発症と進展を抑えるためにー

    槇野博史, 秋山賢次, 横田欣也

    四国新聞 2007年10月28日   2007年

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  • 基礎講座 糖尿病モデル動物 Ⅱ腎症モデル

    佐々木基史, 四方賢一, 槇野博史

    Diabetes Frontier   18 ( 5 )   2007年

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  • 高血圧の精査にて発見されたNSE産生性副腎平滑筋肉種の一例

    後藤順子, 大塚文男, 小寺 亮, 稲垣兼一, 三好智子, 大谷寛之, 鈴木二郎, 三村由香里, 小倉俊郎, 槇野博史

    日本内分泌学会雑誌   83   2007年

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  • リンパ球性漏斗神経葉炎と肺癌脳転移を伴った中枢性尿崩症の一例

    大谷寛之, 大塚文男, 廣田大昌, 三好智子, 稲垣兼一, 鈴木二郎, 後藤順子, 三村由香里, 小倉俊郎, 田淵雅弘, 槇野博史

    日本内分泌学会雑誌   83   2007年

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  • 副腎腺腫の出血・壊死によりユルチゾールの分泌増加を生じたと考えられる一例

    大塚文男, 小寺 亮, 鈴木二郎, 稲垣兼一, 三好智子, 大谷寛之, 後藤順子, 小倉俊郎, 槇野博史

    ACTH RELATED PEPTIDES   18   79 - 80   2007年

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  • MSDを合併した先端巨大症に対するオクトレチオドによる1治療例

    三好智子, 大塚文男, 稲垣兼一, 鈴木二郎, 大谷寛之, 後藤順子, 三村由香里, 小倉俊郎, 景山甚郷, 前田嘉信, 槇野博史

    日本内分泌学会雑誌   83   2007年

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  • 糖尿病性腎症を有する高血圧患者における治療のあり方 JATOSが示唆するものとは

    槇野博史, Kumar Sharma

    LAND VIEW   ( 4 )   2007年

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  • 本邦における糖尿病性腎症の治療戦略-DNETT-Japanに対する期待-

    槇野博史, 鈴木芳樹, 谷澤幸生, 山根公則

    Medical View Point   28 ( 3 )   6 - 7   2007年

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  • 糖尿病合併高血圧症における降圧薬の選択-臓器保護型Ca拮抗薬の可能性についてー

    藤田敏郎, 槇野博史, 羽田勝計, 松尾清一, 今井圓裕, 藤澤智己

    Therapeutic Research   28 ( 4 )   527 - 534   2007年

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  • DNETT-Jpanの取り組み 糖尿病腎症の寛解を目指したチーム医療による集約的治療

    槇野博史, 四方賢一

    週間医学会新聞   ( 2726 )   2007年

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  • ループス腎炎の診断と治療〜腎臓内科の立場から

    槇野博史

    Astellas Sqare 明日の医療を考える   2007年

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  • Downregulation of the β1,3-Galactosyltransherase Gene in Tonsillar B Lymphocytes and Aberrant Lectin Bindings to Tonsillar IgA as a Pathogenesis of IgA as a Pathogenesis of IgA Nephropathy.

    Inoue T, Sugiyama H, Kikumoto Y, Fukuoka N, Maeshima Y, Hattori H, Fukushima K, Nishizaki K, Hiki Y, Makino H

    IgA Nephropathy Today. Contrib Nephrol. Basel,Karger   157   120 - 124   2007年

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  • Elevated serum sFlt-1/Ang-2 ratio in women with preeclampsia

    Kumiko Hirokoshi, Yohei Maeshima, Kazuko Kobayashi, Eiji Matsuura, Hitoshi Sugiyama, Yasushi Yamasaki, Hisashi Masuyama, Yuji Hiramatsu, Hirofumi Makino

    NEPHRON CLINICAL PRACTICE   106 ( 1 )   C43 - C50   2007年

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    記述言語:英語   出版者・発行元:KARGER  

    Background: An imbalance of angiogenesis-associated factors may predispose to preeclampsia. Here, we determined the ratio of serum concentration of soluble fms-like tyrosine kinase 1 (sFlt-1), a natural inhibitor of pro-angiogenic vascular endothelial growth factor (VEGF) relative to angiopoietin-2 (Ang-2), a natural antagonist of angiopoietin-1 (Ang-1) involved in promoting angiogenesis in the presence of VEGF, in women with preeclampsia. Methods: The levels of serum sFlt-1 and Ang-2 were measured by enzyme-linked immunosorbent assay. Results: Significant decrease of serum Ang-2 and the increase of sFlt-1 were observed in women with preeclampsia as compared to healthy pregnant women. The serum sFlt-1/Ang-2 ratio was strikingly increased in preeclamptic women in contrast to healthy pregnant women exhibiting lower value similar to non-pregnant women. The serum sFlt1 concentrations tended to positively correlate with mean blood pressure (BP) in preeclamptic women, but not in healthy pregnant women. A cut-off value > 0.25 in the serum sFlt-1/Ang-2 ratio showed 87.1% sensitivity and 82.8% specificity in differentiating preeclamptic women from healthy pregnant women. Conclusion: The serum sFlt-1/Ang-2 ratio is significantly elevated in preeclamptic women as compared to healthy pregnant women. Remarkable difference of sFlt-1/Ang-2 ratio between these two groups with excellent specificity and sensitivity suggests the clinical usefulness of the serum sFlt-1/Ang-2 ratio in diagnosing and potentially predicting the onset of preeclampsia. Copyright (c) 2007 S. Karger AG, Basel.

    DOI: 10.1159/000101483

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  • Hemophagocytic syndrome associated with fatal veno-occlusive disease in the liver

    Atsuko Nakatsuka, Jun Wada, Ryo Nagase, Masaya Takeda, Tadashi Yoshino, Hirofumi Makino

    INTERNAL MEDICINE   46 ( 8 )   495 - 499   2007年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    A 47-year-old man presented with hemophagocytic syndrome (HPS) without any obvious underlying diseases. On computed tomography, his liver was occupied by multiple ill-defined low intensity lesions. Liver biopsy revealed diffuse infiltration of numerous histiocytes without cytologic atypism and prominent fibrotic changes. These histiocyes showed S100(+), CD68(+), CD1a(-), and lysozyme(+) and Langerhans cell granules were not observed by electron microscopic examination. He failed to respond to immunosuppressive and chemotherapeutic treatments and progressed to severe liver failure. At autopsy, his liver exhibited veno-occulusive disease (VOD). Since VOD is regarded as a rare complication of HPS, the presence of VOD associated with HPS may be easily overlooked.

    DOI: 10.2169/internalmedicine.46.6294

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  • Comparison of Hepatic Enzymes between Japanese Men with and without Metabolic Syndrome.

    Miyatake N, Wada J, Saito T, Nishikawa H, Matsumoto S, Miyachi M, Makino H

    Acta Med. Okayama   61 ( 2 )   99 - 102   2007年

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  • Severe Hypoglycemia Induced by IGF-II Producing Non-Islet Cell Tumor

    Motoko Kanzaki, Hiromi Kashihara, Katsuyuki Kiura, Kazutoshi Murakami, Hiromi Iwagaki, Jun Wada, Hirofumi Makino

    INTERNAL MEDICINE   46 ( 13 )   1061 - 1061   2007年

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    記述言語:英語   掲載種別:速報,短報,研究ノート等(学術雑誌)   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    DOI: 10.2169/internalmedicine.46.6455

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  • 糖尿病における血糖管理

    利根淳仁, 四方賢一, 槇野博史

    岡山県医学会雑誌   119   75 - 77   2007年

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  • 多嚢胞性卵巣症候群を合併した先端巨大症の一例.

    大塚文男, 稲垣兼一, 鈴木二郎, 三好智子, 大谷寛之, 後藤順子, 三村由香里, 小倉俊郎, 槇野博史

    第三回アクロメガリーフォーラム記録集   10   2007年

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  • 足細胞陥入糸球体症に関する国内調査中間報告

    城 謙輔, 田口 尚, 小林 豊, 佐藤 博, 西 慎一, 片渕律子, の村信介, 槇野博史, 斉藤喬雄, 重松秀一

    日本腎臓学会誌   49 ( 2 )   2007年

  • 特集 慢性腎臓病の進行機序と治療 糸球体障害の進展機序と治療戦略

    前島洋平, 槇野博史

    細胞   39 ( 5 )   15 - 18   2007年

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  • 慢性腎炎:診断と治療の進歩 Ⅰ.概念

    杉山 斉, 菊本陽子, 槇野博史

    日本内科学会雑誌   96 ( 5 )   2007年

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  • 腎性貧血と免疫系

    高取優二, 中尾一志, 槇野博史

    腎と透析   62 ( 4 )   2007年

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  • 全身性疾患としての腎臓病の考え方

    杉山 斉, 槇野博史

    綜合臨牀   56 ( 6 )   2007年

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  • DNETT-Japan

    槇野博史, 四方賢一

    医学のあゆみ   220 ( 13 )   2007年

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  • Steroid pulse therapy impaired endothelial function while increasing plasma high molecule adiponectin concentration in patients with IgA nephropathy

    Haruhito Adam Uchida, Yoshio Nakamura, Masanobu Kaihara, Hisanao Norii, Yoshihisa Hanayama, Hitoshi Sugiyama, Yohei Maeshima, Yasushi Yamasaki, Hirofumi Makino

    NEPHROLOGY DIALYSIS TRANSPLANTATION   21 ( 12 )   3475 - 3480   2006年12月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    Background. Decreased plasma adiponectin is associated with impaired endothelial function and, thereby, increased risk for cardiovascular events. Glucocorticoid (GC) affects vascular endothelial cells either favourably or harmfully depending upon the dosages and duration. We examined the effect of GC pulse therapy on vascular endothelial function.
    Methods. Fourteen young patients with IgA nephropathy were evaluated for flow-mediated vasodilation (FMD), plasma levels of adiponectin both in high molecular weight (HMW adiponectin) form and in single molecular form (total adiponectin), hepatocyte growth factor (HGF), asymmetric dimethylarginine (ADMA), and high-sensitive C-reactive protein, before and after a course of GC pulse therapy.
    Results. GC pulse therapy significantly decreased FMD (from 7.2 +/- 2.6 to 5.7 +/- 2.5%, P < 0.01). Meanwhile, plasma adiponectin levels were significantly augmented (total adiponectin: from 10.2 +/- 4.0 to 12.1 +/- 6.3 mu g/ml, P < 0.05; HMW: from 6.5 +/- 3.2 to 7.7 +/- 3.3 mu g/ml, P < 0.05). In parallel, elevated concentrations of serum HGF (from 0.28 +/- 0.12 to 0.63 +/- 0.38 ng/ml, P < 0.01) and plasma ADMA (from 0.45 +/- 0.07 to 0.53 +/- 0.04 nmol/ml, P < 0.05) were observed.
    Conclusions. GC pulse therapy impaired endothelial function while increasing plasma adiponectin levels, which may in turn restore the endothelial function in patients with IgA nephropathy.

    DOI: 10.1093/ndt/gfl423

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  • Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries

    Hiroyuki Kitayama, Yohei Maeshima, Yuki Takazawa, Yoshihiko Yamamoto, Yan Wu, Kunihiro Ichinose, Kumiko Hirokoshi, Hitoshi Sugiyama, Yasushi Yamasaki, Hirofumi Makino

    AMERICAN JOURNAL OF HYPERTENSION   19 ( 7 )   718 - 727   2006年7月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

    Background: Among various angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) play crucial roles in regulating angiogenesis and vascular integrity. Infusion of angiotensin-II (ang II) induces hypertension and focal renal tubulointerstitial injuries. In the present study we investigated the renal expression of VEGF, Ang1, Ang2, and corresponding receptors in association with tubulointerstitial lesions in a rat ang II infusion model.
    Methods: Male Sprague-Dawley (SD) rats received an infusion of ang II or norepinephrine (NE) through osmotic minipumps for 14 days. Angiotensin II type 1 (AT,) or type 2 (AT(2)) receptor antagonist (losartan or PD123319, respectively) or hydralazine was co-administered.
    Results: Interstitial fibrosis, infiltration of monocyte/macrophage, and peritubular capillary rarefaction induced by ang II was significantly attenuated in the losartan- or PD123319-treated groups. Immunoreactivity of VEGF and Ang1 in cortical tubules was increased by ang II and was attenuated by losartan or PD123319. The increase of VEGF induced by ang II was suppressed by losartan, and the increase of Ang1 induced by ang II was inhibited by PD123319 as detected by immunoblot. The increase of flk-1 and flt-1 (VEGF receptors) and tie-2 (Ang1 receptor) induced by ang II was significantly suppressed by PD123319. These alterations were not observed in hydralazine plus ang II or NE-infused animals.
    Conclusions: These results demonstrate that an infusion of ang II induced the expression of VEGF mainly through AT, receptors, and increased the expression of VEGF receptors, tie-2, and Ang1/Ang2 ratio mainly through AT2 receptors. The increase of VEGF/flk-1/flt-1 may be associated with vascular permeability, monocyte/macrophage infiltration, and rarefaction of peritubular capillaries, and the increase of the Ang1/Ang2 ratio may be a compensatory mechanism counteracting the permeability inducing effect of VEGF after ang II infusion. Am J Hypertens 2006;19:718-727 (c) 2006 American Journal of Hypertension, Ltd.

    DOI: 10.1016/j.amjhyper.2005.09.022

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  • Involvement of bone morphogenetic protein-6 in differential regulation of aldosterone production by angiotensin II and potassium in human adrenocortical cells

    Kenichi Inagaki, Fumio Otsuka, Jiro Suzuki, Yoshihiro Kano, Masaya Takeda, Tomoko Miyoshi, Hiroyuki Otani, Yukari Mimura, Toshio Ogura, Hirofumi Makino

    ENDOCRINOLOGY   147 ( 6 )   2681 - 2689   2006年6月

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    記述言語:英語   出版者・発行元:ENDOCRINE SOC  

    Aldosterone production is modified by several growth factors that reside in the adrenal. We have recently reported the existence of a bone morphogenetic protein (BMP) system in human adrenocortical cells, in which BMP-6 augments aldosterone synthesis. Here, we investigated functional roles of BMP-\6, focusing on the differential regulation of aldosterone synthesis induced by angiotensin (Ang) II and potassium (K). In human adrenocortical H295R cells, BMP-6 augmented Ang II-induced CYP11B2 transcription and mRNA and aldosterone roduction but had no effect on K-induced aldosterone production. Inhibition of endogenous BMP-6 action by neutralizing antibodies impaired aldosterone production induced by Ang II but not that induced by K. Blockage of ligand-receptor binding using extracellular domain (ECD) of BMP type I receptors revealed that ECDs to activin receptor-like kinase (ALK)-2 and ALK-3 significantly reduced the aldosterone production induced by Ang II. None of the type I-receptor ECDs tested had any effect on K-induced aldosterone levels. Overexpression of a dominant negative-activin type II receptor construct selectively decreased Ang II-induced aldosterone production without having any effect on K-induced aldosterone production. BMP type II receptor-dominant negative had no effect on aldosterone induced by either Ang II or K. These results infer that BMP-6 acts through ALK-2, ALK-3, and activin type II receptor receptors in adrenocortical cells. BMP-6 pretreatment extends the induction of ERK1/2 phosphorylation by Ang II and treatment with ECDs to ALK-2 and ALK-3 impaired Ang II-induced ERK phosphorylation. The specific inhibitor of ERK activation, U0126, suppressed the activation of CYP11B2 transcription induced by BMP-6 without affecting Smad phosphorylation and Tlx2-Luc activity. Collectively, the endogenous BMP-6 system plays critical roles in aldosterone production between Ang II and K through ERK signaling pathway.

    DOI: 10.1210/en.2005-1250

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  • Mutual regulation of follicle-stimulating hormone signaling and bone morphogenetic protein system in human granulosa cells

    T Miyoshi, F Otsuka, Suzuki, I, M Takeda, K Inagaki, Y Kano, H Otani, Y Mimura, T Ogura, H Makino

    BIOLOGY OF REPRODUCTION   74 ( 6 )   1073 - 1082   2006年6月

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    記述言語:英語   出版者・発行元:SOC STUDY REPRODUCTION  

    Bone morphogenetic proteins (BMPs) play critical roles in folliculogenesis by modulating the actions of follicle-stimulating hormone (FSH) in the ovary. However, the effects of FSH on the BMP system remain unknown. Here, we have investigated the effects of FSH on BMP signaling using the human granulosa-like tumor cell line KGN. KGN cells express BMP type 1 and type II receptors and the BMP signaling molecules SMADs. FSH administration upregulated BMP type IA (BMPR1A) and IB (BMPR1B) receptors, activin type II receptor (ACVR2), and BMP type II receptor (BMPR2). FSH also augmented SMAD1 and SMAD5 expression, and conversely, FSH suppressed the expression of the inhibitory SMADs, SMAD6 and SMAD7. Bioassays revealed that FSH enhances BMP-induced SMAD1/5/8 phosphorylation and cellular DNA synthesis induced by BMP6 and BMP7. Since overexpression of BMPR1A and BMPR1B, but not SMADs, significantly enhanced the BMP responses, these type I receptors were revealed to be limiting factors for BMP signaling in KGN cells. BMPs significantly suppressed progesterone synthesis induced by forskolin and dibutyryl-cAMP (BtcAMP) but had no effect on estradiol induced by the same factors. KGN cAMP levels induced by forskolin were not altered by BMPs, suggesting that BMPs regulate steroidogenesis at a level downstream of cAMP synthesis in KGN cells. In this regard, BMPs specifically reduced the STAR transcription, whereas the levels of CYP11A, HSD3B2, and CYP19 stimulated by forskolin as well as BtcAMP were not altered. Collectively, the two major factors, FSH-cAMP pathway and BMP system, are reciprocally and functionally linked. Given that BMPs downregulate FSH receptors in KGN cells, this interaction may contribute to finetuning of the mutual sensitivity toward BMP ligands and FSH.

    DOI: 10.1095/biolreprod.105.047969

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  • Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms

    T Okada, J Wada, K Hida, J Eguchi, Hashimoto, I, M Baba, A Yasuhara, K Shikata, H Makino

    DIABETES   55 ( 6 )   1666 - 1677   2006年6月

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    記述言語:英語   出版者・発行元:AMER DIABETES ASSOC  

    Thiazolidinediones are ligands for peroxisome proliferator-activated receptor-activated receptor (PPAR)-gamma, widely used as insulin sensitizer in type 2 diabetic patients and implicated in apoptosis, cell proliferation, and cell cycle regulation. Here, the effect of thiazolidinediones on G1-phase cell cycle arrest, the hallmark in diabetic nephropathy, was investigated. Eight-week-old male Otsuka Long-Evans Tokushima fatty rats were treated with pioglitazone (1 mg kg body wt(-1) (.) day(-1)) until 50 weeks of age and compared with insulin treatment. Although similar HbA(1c) levels were observed in both groups, pioglitazone significantly inhibited glomerular hypertrophy and mesangial matrix expansion and reduced urinary albumin excretion compared with the insulin-treated group. In addition, pioglitazone significantly reduced the number of glomerular p27(Kip1)-positive cells. Because prominent expression of PPAR-gamma was observed in podocytes in glomeruli and cultured cells, conditionally immortalized mouse podocyte cells were cultured under 5.5 and 25 mmol/l D-glucose supplemented with pioglitazone. Pioglitazone inhibited cell hypertrophy revealed by [H-3]thymidine and [H-3]proline incorporation, and pioglitazone reversed high glucose-induced G1-phase cell cycle arrest, i.e., an increase in G0/G1 phase and decrease in S and G2 phases. Pioglitazone suppressed high glucose-induced phosphorylation of p44/42 mitogen-activated protein kinase and reduced Bcl-2 and P27(Kip1) protein levels. Besides glucose-lowering action, pioglitazone ameliorates diabetic nephropathy via cell cycle-dependent mechanisms.

    DOI: 10.2337/db05-1285

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  • Therapeutic approach for diabetic nephropathy using gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production

    Yanling Zhang, Jun Wada, Izumi Hashimoto, Jun Eguchi, Akihiro Yasuhara, Yashpal S. Kanwar, Kenichi Shikata, Hirofumi Makino

    JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY   17 ( 4 )   1090 - 1101   2006年4月

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    記述言語:英語   出版者・発行元:AMERICAN SOCIETY NEPHROLOGY  

    Hyperglycemia-induced overproduction of mitochondrial reactive oxygen species has emerged as a major player in diabetic vascular complications. Mammalian translocase of inner mitochondrial membrane 44 (TIM44) was identified by upregulation in diabetic mouse kidneys. TIM44 functions as a membrane anchor of mitochondrial heat-shock protein 70 (mtHsp70) to TIM23 complex and is involved in the import of mitochondria-targeted preproteins into mitochondrial matrix. The process is dependent on inner membrane potential and ATP hydrolysis on ATPase domain of mitochondrial heat-shock protein 70. Hemagglutination virus of Japan-envelope vector that carries pcDNA3.1 plasmid that contains the full-length cDNA of TIM44 and control plasmid were injected weekly into the tail vein of uninephrectomized streptozotocin-induced diabetic CD-1 mice. The gene delivery alleviated proteinuria and renal hypertrophy at 8 wk after the injection, inhibited renal cell proliferation and apoptosis, and suppressed superoxide production. In vitro experiments, using human proximal tubular (HK2) cells, revealed that the gene delivery of TIM44 reversed high glucose-induced metabolic and cellular abnormalities such as enhanced reactive oxygen species production, increased ATP contents, alterations in inner membrane potential, increased cell proliferation, and apoptosis. Transfection with siRNA and expressing vector of TIM44 revealed that TIM44 facilitates import of antioxidative enzymes such as superoxide dismutase and glutathione peroxidase into mitochondria. The gene delivery of TIM44 therefore seems to be beneficial for the maintenance of mitochondrial function and is a novel therapeutic approach for diabetic nephropathy.

    DOI: 10.1681/ASN.2005111148

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  • Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis

    K Sunahori, M Yamamura, J Yamana, K Takasugi, M Kawashima, H Makino

    ARTHRITIS AND RHEUMATISM   54 ( 1 )   97 - 104   2006年1月

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    記述言語:英語   出版者・発行元:WILEY-LISS  

    Objective. The accumulation of advanced glycation end products (AGEs), S100A12, and high mobility group box chromosomal protein I has been associated with joint inflammation in rheumatoid arthritis (RA). This study was undertaken to determine the induction of the receptor for these proteins, termed receptor for AGEs (RAGE), in synovial tissue (ST) macrophages from RA patients.
    Methods. RAGE and CD68 expression in ST were determined by 2-color immunofluorescence labeling. Cell surface and messenger RNA (mRNA) expression of RAGE were examined by flow cytometry and reverse transcriptase-polymerase chain reaction (PCR) or real-time PCR, respectively.
    Results. CD68+ lining macrophages, like the vasculature, expressed high levels of RAGE in inflamed ST from RA patients. RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis. RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST CD4+ T cells and synovial fibroblasts stimulated with tumor necrosis factor a and interieukin-1 beta (IL-1 beta). Cell surface RAGE was highly induced on normal monocytes after a 24-hour incubation with a 20% concentration of RA ST cell culture supernatants. RAGE mRNA expression in adherent monocytes was augmented by various cytokines, most potently by IL-1 beta.
    Conclusion. These results indicate that RAGE overexpression in lining macrophages may be induced, at least in part, by cytokines such as IL-1, leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints.

    DOI: 10.1002/art.21524

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  • CKDの対策と治療

    藤田敏郎, 菱田 明, 槇野博史, 松尾清一

    Pharma Medica   24,10,106-111   2006年

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  • Relationship between metabolic syndrome and cigarette smoking in the Japanese population

    Nobuyuki Miyatake, Jun Wada, Yuriko Kawasaki, Kenji Nishii, Hirofumi Makino, Takeyuki Numata

    INTERNAL MEDICINE   45 ( 18 )   1039 - 1043   2006年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Objective We investigated the link between metabolic syndrome and cigarette smoking in the Japanese population.
    Methods A total of 3,177 Japanese subjects aged 20-79 years were recruited in a cross-sectional clinical investigation study. Habits of cigarette smoking were obtained at interviews by well-trained staff. The diagnosis of metabolic syndrome was based on the new criterion in Japan.
    Results Four hundred and forty men (35.3%) and 142 women (7.4%) were current smokers. Three hundred thirty four men (26.8%) and 69 women (3.6%) were diagnosed as metabolic syndrome. The prevalence of current smoker in subjects with metabolic syndrome was significantly higher than in subjects with non-metabolic syndrome in men with and without adjustment for age. The prevalence of metabolic syndrome in men with Brinkman index >= 600 was significantly higher than that in men with Brinkman index<600.
    Conclusion The present study indicated that cigarette smoking may be an important modifiable factor in Japanese men with metabolic syndrome.

    DOI: 10.2169/internalmedicine.45.1850

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  • Relationship between metabolic syndrome and proteinuria in the Japanese population

    Nobuyuki Miyatake, Jun Wada, Yuriko Kawasaki, Sumiko Matsumoto, Hirofumi Makino, Takeyuki Numata

    INTERNAL MEDICINE   45 ( 9 )   599 - 603   2006年

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    記述言語:英語   出版者・発行元:JAPAN SOC INTERNAL MEDICINE  

    Objective We investigated the link between metabolic syndrome and proteinuria in Japanese.
    Methods A total of 12,023 Japanese subjects, aged 20-79 years, were recruited in a cross-sectional clinical investigation study. From this group, we used data of 2,121 subjects for further investigation. Proteinuria was measured by using urine strip devices. The diagnosis of metabolic syndrome was based on the new criterion in Japan.
    Results In the first analysis, 224 men (6.0%) and 359 women (4.3%) were diagnosed as trace positive (+/-) and 155 men (4.1%) and 147 women (1.8%) were diagnosed as positive (+<=) with proteinuria. In the second analysis, 264 men (29.7%) and 45 women (3.7%) were diagnosed as metabolic syndrome. Prevalence of proteinuria in subjects with metabolic syndrome was significantly higher than that in subjects with non metabolic syndrome in both sexes. In addition, the atherogenic index was significantly higher in subjects with metabolic syndrome than in subjects with non-metabolic syndrome.
    Conclusion The present study indicated that metabolic syndrome might be an important factor in the etiology of proteinuria in Japanese.

    DOI: 10.2169/internalmedicine.45.1681

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  • The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis

    Katsue Sunahori, Masahiro Yamamura, Jiro Yamana, Kouji Takasugi, Masanori Kawashima, Hiroshi Yamamoto, Walter J. Chazin, Yuichi Nakatani, Satoru Yui, Hirofumi Makino

    ARTHRITIS RESEARCH & THERAPY   8 ( 3 )   2006年

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    S100A8 and S100A9, two Ca(2+)-binding proteins of the S100 family, are secreted as a heterodimeric complex (S100A8/A9) from neutrophils and monocytes/macrophages. Serum and synovial fluid levels of S100A8, S100A9, and S100A8/A9 were all higher in patients with rheumatoid arthritis ( RA) than in patients with osteoarthritis (OA), with the S100A8/A9 heterodimer being prevalent. By two-color immunofluorescence labeling, S100A8/A9 antigens were found to be expressed mainly by infiltrating CD68(+) macrophages in RA synovial tissue (ST). Isolated ST cells from patients with RA spontaneously released larger amounts of S100A8/A9 protein than did the cells from patients with OA. S100A8/A9 complexes, as well as S100A9 homodimers, stimulated the production of proinflammatory cytokines, such as tumor necrosis factor alpha, by purified monocytes and in vitro-differentiated macrophages. S100A8/A9-mediated cytokine production was suppressed significantly by p38 mitogen-activated protein kinase ( MAPK) inhibitors and almost completely by nuclear factor kappa B (NF kappa B) inhibitors. NF-kappa B activation was induced in S100A8/A9-stimulated monocytes, but this activity was not inhibited by p38 MAPK inhibitors. These results indicate that the S100A8/A9 heterodimer, secreted extracellularly from activated tissue macrophages, may amplify proinflammatory cytokine responses through activation of NF-kappa B and p38 MAPK pathways in RA.

    DOI: 10.1186/ar1939

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  • Induction of tumour necrosis factor receptor-expressing macrophages by interleukin-10 and macrophage colony-stimulating factor in rheumatoid arthritis

    Koji Takasugi, Masahiro Yamamura, Mitsuhiro Iwahashi, Fumio Otsuka, Jiro Yamana, Katsue Sunahori, Masanori Kawashima, Masao Yamada, Hirofumi Makino

    ARTHRITIS RESEARCH & THERAPY   8 ( 4 )   2006年

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    記述言語:英語   出版者・発行元:BIOMED CENTRAL LTD  

    Despite its potent ability to inhibit proinflammatory cytokine synthesis, interleukin (IL)-10 has a marginal clinical effect in rheumatoid arthritis ( RA) patients. Recent evidence suggests that IL-10 induces monocyte/ macrophage maturation in cooperation with macrophage-colony stimulating factor (M-CSF). In the present study, we found that the inducible subunit of the IL-10 receptor (IL-10R), type 1 IL-10R (IL-10R1), was expressed at higher levels on monocytes in RA than in healthy controls, in association with disease activity, while their expression of both type 1 and 2 tumour necrosis factor receptors (TNFR1/2) was not increased. The expression of IL-10R1 but not IL-10R2 was augmented on monocytes cultured in the presence of RA synovial tissue (ST) cell culture supernatants. Cell surface expression of TNFR1/2 expression on monocytes was induced by IL-10, and more efficiently in combination with M-CSF. Two-color immunofluorescence labeling of RA ST samples showed an intensive coexpression of IL-10R1, TNFR1/2, and M-CSF receptor in CD68(+) lining macrophages. Adhered monocytes, after 3-day preincubation with IL-10 and M-CSF, could produce more IL-1 beta and IL-6 in response to TNF-alpha in the presence of dibutyryl cAMP, as compared with the cells preincubated with or without IL-10 or M-CSF alone. Microarray analysis of gene expression revealed that IL-10 activated various genes essential for macrophage functions, including other members of the TNFR superfamily, receptors for chemokines and growth factors, Toll-like receptors, and TNFR-associated signaling molecules. These results suggest that IL-10 may contribute to the inflammatory process by facilitating monocyte differentiation into TNF-alpha-responsive macrophages in the presence of M-CSF in RA.

    DOI: 10.1186/ar2015

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  • Elevated serum monocyte chemoattractant protein-4 and chronic inflammation in overweight subjects.

    Hashimoto I, Wada J, Hida A, Bada M, Miyake N, Eguchi J, Shikata K, Makino H

    Obesity   2006年

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  • メタボリックシンドロームと腎

    槇野博史

    ドクターサロン腎臓病への新しいアプローチ(Ⅱ)   50,1,61-64   2006年

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  • Altered levels of adipocytokines in association with insulin resistance in patients with systemic lupus erythematosus.

    Sada KE, Yamasaki Y, Maruyama M, Sugiyama H, Yamamura M, Maeshima Y, Makino H

    J Rheumatol   2006年

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  • 成体腎組織幹・前駆細胞の組織修復への関与

    木野村賢, 喜多村真治, 前島洋平, 槇野博史

    腎臓   28,3,171-174   2006年

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  • 傷害尿細管の修復 分子腎臓病学-分子生物学的アプローチと分子病態生理学-

    喜多村真治, 前島洋平, 槇野博史

    日本臨牀   65,2,58-61   2006年

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  • 糖尿病性腎症の早期治療の重要性とARB

    槇野博史

    最新の疾患別PTM治療マニュアル   6月号   2006年

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  • 腎症進展における糸球体上皮細胞障害の意義

    前島洋平, 一瀬邦弘, 山本佳彦, 槇野博史

    分子糖尿病学の進歩-基礎から臨床まで-   1,1,162-167   2006年

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  • 糖尿病性腎症

    中尾一志, 四方泰史, 槇野博史

    糖尿病ライフ さかえ   7月号,16-22   2006年

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  • 特集降圧薬処方のノウハウ メタボリックシンドローム患者の降圧薬処方のノウハウ

    村上和敏, 和田 淳, 槇野博史

    成人病と生活習慣病   36,4,399-403   2006年

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  • 腎疾患と臨床検査 ANCAおよび免疫関連検査(補体、抗核抗体など)

    木野村賢, 佐田憲映, 杉山 斉, 槇野博史

    臨床検査   50,5,537-541   2006年

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  • 間質性腎炎・ネフローゼ症候群を中心に

    丸山美江, 杉山 斉, 槇野博史

    臨床と研究   83,8,1191-1194   2006年

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  • 糖尿病合併症の病理:腎合併症

    利根淳仁, 四方賢一, 槇野博史

    糖尿病の病理 病理と臨床   24,7,720-726   2006年

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  • 炎症を制御する薬剤

    利根淳仁, 四方賢一, 槇野博史

    Diabetes Frontier   17,4,497-502   2006年

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  • アルドステロンと腎臓

    大谷寛之, 大塚文男, 槇野博史

    治療学   40,8,837-840   2006年

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  • メタボリックシンドロームと腎機能障害

    吉川理津子, 和田 淳, 槇野博史

    日本医師会雑誌   135,6,MS21-24   2006年

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  • 特集 メタボリック症候群と腎障害 微量アルブミン尿の意義と管理

    吉川理津子, 和田 淳, 槇野博史

    腎と透析   60,4,616-619   2006年

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  • CKDの定義と分類

    田邊克幸, 前島洋平, 槇野博史

    腎臓   29,2,78-81   2006年

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  • 先端巨大症患者の頭痛におけるオクトレオチドの効果

    三好智子, 大塚文男, 鈴木二郎, 稲垣兼一, 小倉俊郎, 溝渕知司, 槇野博史

    ホルモンと臨床 「内分泌クリニカル・カンファランス46」   54,40-44   2006年

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  • 糖尿病