研究者詳細 - 江口　潤

論文 - 江口　潤

分割表示 93 件中 41 - 60 件目／全件表示 >>

SAP療法の治療反応性を予見する患者像の検討

利根淳仁, 勅使川原早苗, 宮本聡, 江口潤, 中司敦子, 樋口千草, 小川大輔, 四方賢一, 和田淳

糖尿病 60 ( Suppl.1 ) S - 390 2017年4月

Marked hypertriglyceridemia induced by interferon-β1a therapy in a clinically isolated syndrome patient. 国際誌

Yuko Kawahara, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Keiichiro Tsunoda, Mami Takemoto, Nozomi Hishikawa, Jun Eguchi, Koji Abe

Journal of the neurological sciences 373 144 - 146 2017年2月

IRF3 promotes adipose inflammation and insulin resistance and represses browning. 国際誌

Manju Kumari, Xun Wang, Louise Lantier, Anna Lyubetskaya, Jun Eguchi, Sona Kang, Danielle Tenen, Hyun Cheol Roh, Xingxing Kong, Lawrence Kazak, Rasheed Ahmad, Evan D Rosen

The Journal of clinical investigation 126 ( 8 ) 2839 - 54 2016年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

The chronic inflammatory state that accompanies obesity is a major contributor to insulin resistance and other dysfunctional adaptations in adipose tissue. Cellular and secreted factors promote the inflammatory milieu of obesity, but the transcriptional pathways that drive these processes are not well described. Although the canonical inflammatory transcription factor NF-κB is considered to be the major driver of adipocyte inflammation, members of the interferon regulatory factor (IRF) family may also play a role in this process. Here, we determined that IRF3 expression is upregulated in the adipocytes of obese mice and humans. Signaling through TLR3 and TLR4, which lie upstream of IRF3, induced insulin resistance in murine adipocytes, while IRF3 knockdown prevented insulin resistance. Furthermore, improved insulin sensitivity in IRF3-deficient mice was associated with reductions in intra-adipose and systemic inflammation in the high fat-fed state, enhanced browning of subcutaneous fat, and increased adipose expression of GLUT4. Taken together, the data indicate that IRF3 is a major transcriptional regulator of adipose inflammation and is involved in maintaining systemic glucose and energy homeostasis.

DOI： 10.1172/JCI86080

Inhibition of SGLT2 alleviates diabetic nephropathy by suppressing high glucose-induced oxidative stress in type 1 diabetic mice. 国際誌

Takashi Hatanaka, Daisuke Ogawa, Hiromi Tachibana, Jun Eguchi, Tatsuyuki Inoue, Hiroshi Yamada, Kohji Takei, Hirofumi Makino, Jun Wada

Pharmacology research & perspectives 4 ( 4 ) e00239 2016年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

It is unclear whether the improvement in diabetic nephropathy by sodium glucose cotransporter 2 (SGLT2) inhibitors is caused by a direct effect on SGLT2 or by the improvement in hyperglycemia. Here, we investigated the effect of dapagliflozin on early-stage diabetic nephropathy using a mouse model of type 1 diabetes and murine proximal tubular epithelial cells. Eight-week-old Akita mice were treated with dapagliflozin or insulin for 12 weeks. Body weight, urinary albumin excretion, blood pressure, as well as levels of blood glucose and hemoglobin A1c were measured. Expansion of the mesangial matrix, interstitial fibrosis, and macrophage infiltration in kidneys were evaluated by histology. Oxidative stress and apoptosis were evaluated in kidneys and cultured proximal tubular epithelial cells. Compared with nontreated mice, dapagliflozin and insulin decreased blood glucose and hemoglobin A1c levels equally. Urine volume and water intake increased significantly in the dapagliflozin-treated group compared with those in the insulin-treated group, but there were no differences in body weight or blood pressure between the two groups. Macrophage infiltration and fibrosis in renal interstitium improved significantly in the dapagliflozin group compared with the insulin group. Oxidative stress was attenuated by dapagliflozin, and suppression occurred in a dose-dependent manner. RNAi knockdown of SGLT2 resulted in reduced oxidative stress. Dapagliflozin ameliorates diabetic nephropathy by suppressing hyperglycemia-induced oxidative stress in a manner independent of hyperglycemia improvement in Akita mice. Our findings suggest that dapagliflozin may be a novel therapeutic approach for the treatment of diabetic nephropathy.

DOI： 10.1002/prp2.239

Antiobesity Action of ACAM by Modulating the Dynamics of Cell Adhesion and Actin Polymerization in Adipocytes. 国際誌

Kazutoshi Murakami, Jun Eguchi, Kazuyuki Hida, Atsuko Nakatsuka, Akihiro Katayama, Miwa Sakurai, Haruki Choshi, Masumi Furutani, Daisuke Ogawa, Kohji Takei, Fumio Otsuka, Jun Wada

Diabetes 65 ( 5 ) 1255 - 67 2016年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Coxsackie virus and adenovirus receptor-like membrane protein (CLMP) was identified as the tight junction-associated transmembrane protein of epithelial cells with homophilic binding activities. CLMP is also recognized as adipocyte adhesion molecule (ACAM), and it is upregulated in mature adipocytes in rodents and humans with obesity. Here, we present that aP2 promoter-driven ACAM transgenic mice are protected from obesity and diabetes with the prominent reduction of adipose tissue mass and smaller size of adipocytes. ACAM is abundantly expressed on plasma membrane of mature adipocytes and associated with formation of phalloidin-positive polymerized form of cortical actin (F-actin). By electron microscopy, the structure of zonula adherens with an intercellular space of ∼10-20 nm was observed with strict parallelism of the adjoining cell membranes over distances of 1-20 μm, where ACAM and γ-actin are abundantly expressed. The formation of zonula adherens may increase the mechanical strength, inhibit the adipocyte hypertrophy, and improve the insulin sensitivity.

DOI： 10.2337/db15-1304

糖尿病性腎症におけるVaspinの意義

中司敦子, 三瀬広記, 江口潤, 和田淳

日本腎臓学会誌 58 ( 3 ) 262 - 262 2016年5月

Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis. 国際誌

Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe, Jun Wada

Scientific reports 6 21721 - 21721 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/- mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/- mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4α resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

DOI： 10.1038/srep21721

The gender specific risk factors for prolonged hospitalization due to acute pyelonephritis in a Japanese tertiary emergency center. 国際誌

Risa Muneishi, Ryuta Tanimoto, Koichiro Wada, Philip Hsiao, Jun Eguchi, Motoo Araki, Toyohiko Watanabe, Yasutomo Nasu, Naoki Akebi

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 22 ( 2 ) 108 - 11 2016年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: The aim of this study is to characterize the potential differences between male and female patients with acute pyelonephritis (AP) and to predict the severity of AP based on the length of hospital stay. METHODS: We conducted a retrospective medical chart review of 172 consecutive adult patients who were hospitalized in Tsuyama Central Hospital due to AP from January 2007 through June 2012. We analyzed the length of hospital stay by the proportional hazard model. RESULTS: A total of 172 patients were identified who were admitted to our hospital with a diagnosis of AP. Of them, 62% (106/172) were female. Except for urological malignancy, there was no significant difference between men and women in underlying disease. Out of 26 variables, univariate analysis in male showed that only urolithiasis (OR 1.75, p = 0.0294) was significantly associated with longer hospital stay, while septic shock (OR 3.18, P = 0.003), urological malignancy (OR 2.94, P = 0.002), age over 65 (OR 1.66, p = 0.018) and neurogenic bladder (OR 1.92, p = 0.014) were all associated with longer hospital stay in female patients. CONCLUSIONS: This is the first report to identify the risk factors for prolonged hospital stay for the patients who were admitted with AP in the Japanese population. The risk factors causing prolonged hospital stay were totally different between males and females. Reviewing the medical history based on sex gender might enable a clinician to predict the severity of acute pyelonephritis during the initial evaluation.

DOI： 10.1016/j.jiac.2015.11.007

Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis. 国際誌

Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Tomokazu Nunoue, Kazuyuki Hida, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto, Hiroshi Kiyonari, Hirofumi Makino, Jun Wada

Scientific reports 5 16920 - 16920 2015年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.

DOI： 10.1038/srep16920

Translocase of inner mitochondrial membrane 44 alters the mitochondrial fusion and fission dynamics and protects from type 2 diabetes. 国際誌

Yu Wang, Akihiro Katayama, Takahiro Terami, Xiaoying Han, Tomokazu Nunoue, Dongxiao Zhang, Sanae Teshigawara, Jun Eguchi, Atsuko Nakatsuka, Kazutoshi Murakami, Daisuke Ogawa, Yasuhide Furuta, Hirofumi Makino, Jun Wada

Metabolism: clinical and experimental 64 ( 6 ) 677 - 88 2015年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: In obesity and type 2 diabetes, the impairment of mitochondrial function in white adipose tissue (WAT) is linked to a reduction in whole body insulin sensitivity. Timm44 is upregulated in the kidneys of streptozotocin-induced diabetic mice. In the inner mitochondrial membrane, Timm44 anchors mitochondrial heat-shock protein 70 (mtHsp70) to the translocase of inner mitochondrial membrane 23 (TIM23) complex and facilitates the import of mitochondria-targeted preproteins into the mitochondrial matrix dependent on the inner membrane potential and ATP hydrolysis on ATPase domain of mtHsp70. METHODS: We generated the aP2-promoter driven Timm44 transgenic (Tg) mouse model and investigated whether Timm44 Tg mice fed high-fat/high-sucrose (HFHS) chow are protected from type 2 diabetes and obesity. RESULTS: The body weight of aP2-promoter driven Timm44 Tg mice was lower than that of wild type mice, and insulin sensitivity was greater in Timm44 Tg mice than in wild type mice. Although WAT weight was not altered in Timm44 Tg mice fed HFHS chow, adipocyte size was reduced, and mitochondrial fusion associated with decreased expression of fission genes, such as Dnm1l and Fis1, was observed. In addition, when fed standard (STD) chow, the expressions of the fusion genes Opa1, Mfn1 and Mfn2, and Mfn1 were significantly increased in Timm44 Tg mice compared to wild type mice, and fused mitochondria were also observed in Timm44 Tg mice fed STD chow. CONCLUSIONS: The Timm44 gene may be a new target for the treatment of type 2 diabetes.

DOI： 10.1016/j.metabol.2015.02.004

Identification of circulating miR-101, miR-375 and miR-802 as biomarkers for type 2 diabetes. 国際誌

Chigusa Higuchi, Atsuko Nakatsuka, Jun Eguchi, Sanae Teshigawara, Motoko Kanzaki, Akihiro Katayama, Satoshi Yamaguchi, Naoto Takahashi, Kazutoshi Murakami, Daisuke Ogawa, Sakiko Sasaki, Hirofumi Makino, Jun Wada

Metabolism: clinical and experimental 64 ( 4 ) 489 - 97 2015年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice. BASIC PROCEDURES: We selected four miRNAs, miR-101, miR-335, miR-375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT). MAIN FINDINGS: The serum concentrations of miRNAs, log(10)miR-101, log(10)miR-375, and log(10)miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41±2.01 v.s. -0.57±1.05 (P=1.36×10(-5)), 0.20±0.58 v.s. 0.038±1.00 (P=3.06×10(-6)), and 2.45±1.27 v.s. 0.97±0.98 (P=0.014), respectively). The log(10)miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (-1.08±1.35 v.s. -0.38±1.21 (P=0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants. PRINCIPAL CONCLUSIONS: The present findings demonstrated that the circulating miR-101, miR-375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes.

DOI： 10.1016/j.metabol.2014.12.003

Structural design and synthesis of arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists based on the helix12-folding inhibition hypothesis. 国際誌

Masao Ohashi, Kanae Gamo, Yuta Tanaka, Minoru Waki, Yoko Beniyama, Kenji Matsuno, Jun Wada, Masafumi Tenta, Jun Eguchi, Makoto Makishima, Nobuyasu Matsuura, Takuji Oyama, Hiroyuki Miyachi

European journal of medicinal chemistry 90 53 - 67 2015年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are candidates for treatment of type 2 diabetes, obesity and osteoporosis. However, few rational design strategies are currently available. Here, we utilized the helix12 (H12)-folding inhibition hypothesis, in combination with our previously determined X-ray crystal structure of PPARγ agonist MEKT-21 (6) complexed with the PPARγ ligand-binding domain, to design and develop a potent phenylalkynyl amide-type PPARγ antagonist 9i, focusing initially on pinpoint structural modification of the propanoic acid moiety of 6. Since 9i retained very weak, but distinct, PPARγ agonist activity, we next modified the distal benzene ring of 9i, aiming to delete the residual PPARγ agonist activity while retaining the antagonist activity. Introduction of a chlorine atom at the 2-position of the distal benzene ring afforded 9p, which exhibited potent, PPARγ-selective full antagonist activity without detectable agonist activity. We found that 9p stabilized the corepressor-PPARγ complex and suppressed basal PPARγ activity. This compound showed anti-adipogenesis activity at the cellular level. This agonist-antagonist switching concept based on the H12-folding inhibition hypothesis should also be applicable for designing other classes of PPARγ full antagonists.

DOI： 10.1016/j.ejmech.2014.11.017

2型糖尿病の経過中にBasedow病を発症した1例

布上朋和, 江口潤, 寺見隆宏, 田中景子, 平松澄恵, 小松原基志, 和田淳, 四方賢一, 槇野博史

糖尿病 57 ( 8 ) 654 - 654 2014年8月

Metallothionein deficiency exacerbates diabetic nephropathy in streptozotocin-induced diabetic mice. 国際誌

Hiromi Tachibana, Daisuke Ogawa, Norio Sogawa, Masato Asanuma, Ikuko Miyazaki, Naoto Terami, Takashi Hatanaka, Chikage Sato Horiguchi, Atsuko Nakatsuka, Jun Eguchi, Jun Wada, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

American journal of physiology. Renal physiology 306 ( 1 ) F105-15 2014年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Oxidative stress and inflammation play important roles in diabetic complications, including diabetic nephropathy. Metallothionein (MT) is induced in proximal tubular epithelial cells as an antioxidant in the diabetic kidney; however, the role of MT in renal function remains unclear. We therefore investigated whether MT deficiency accelerates diabetic nephropathy through oxidative stress and inflammation. Diabetes was induced by streptozotocin injection in MT-deficient (MT(-/-)) and MT(+/+) mice. Urinary albumin excretion, histological changes, markers for reactive oxygen species (ROS), and kidney inflammation were measured. Murine proximal tubular epithelial (mProx24) cells were used to further elucidate the role of MT under high-glucose conditions. Parameters of diabetic nephropathy and markers of ROS and inflammation were accelerated in diabetic MT(-/-) mice compared with diabetic MT(+/+) mice, despite equivalent levels of hyperglycemia. MT deficiency accelerated interstitial fibrosis and macrophage infiltration into the interstitium in the diabetic kidney. Electron microscopy revealed abnormal mitochondrial morphology in proximal tubular epithelial cells in diabetic MT(-/-) mice. In vitro studies demonstrated that knockdown of MT by small interfering RNA enhanced mitochondrial ROS generation and inflammation-related gene expression in mProx24 cells cultured under high-glucose conditions. The results of this study suggest that MT may play a key role in protecting the kidney against high glucose-induced ROS and subsequent inflammation in diabetic nephropathy.

DOI： 10.1152/ajprenal.00034.2013

Pemt deficiency ameliorates endoplasmic reticulum stress in diabetic nephropathy. 国際誌

Mayu Watanabe, Atsuko Nakatsuka, Kazutoshi Murakami, Kentaro Inoue, Takahiro Terami, Chigusa Higuchi, Akihiro Katayama, Sanae Teshigawara, Jun Eguchi, Daisuke Ogawa, Eijiro Watanabe, Jun Wada, Hirofumi Makino

PloS one 9 ( 3 ) e92647 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）

Phosphatidylethanolamine N-methyltransferase (Pemt) catalyzes the methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) mainly in the liver. Under an obese state, the upregulation of Pemt induces endoplasmic reticulum (ER) stress by increasing the PC/PE ratio in the liver. We targeted the Pemt gene in mice to explore the therapeutic impact of Pemt on the progression of diabetic nephropathy and diabetes, which was induced by the injection of streptozotocin (STZ). Although the blood glucose levels were similar in STZ-induced diabetic Pemt+/+ and Pemt-/-mice, the glomerular hypertrophy and albuminuria in Pemt-/- mice were significantly reduced. Pemt deficiency reduced the intraglomerular F4/80-positive macrophages, hydroethidine fluorescence, tubulointerstitial fibrosis and tubular atrophy. The expression of glucose-regulated protein-78 (GRP78) was enriched in the renal tubular cells in STZ-induced diabetic mice, and this was ameliorated by Pemt deficiency. In mProx24 renal proximal tubular cells, the treatment with ER-stress inducers, tunicamycin and thapsigargin, increased the expression of GRP78, which was reduced by transfection of a shRNA lentivirus for Pemt (shRNA-Pemt). The number of apoptotic cells in the renal tubules was significantly reduced in Pemt-/- diabetic mice, and shRNA-Pemt upregulated the phosphorylation of Akt and decreased the cleavage of caspase 3 and 7 in mProx24 cells. Taken together, these findings indicate that the inhibition of Pemt activity ameliorates the ER stress associated with diabetic nephropathy in a model of type 1 diabetes and corrects the functions of the three major pathways downstream of ER stress, i.e. oxidative stress, inflammation and apoptosis.

DOI： 10.1371/journal.pone.0092647

Nuclear hormone receptor expression in mouse kidney and renal cell lines. 国際誌

Daisuke Ogawa, Jun Eguchi, Jun Wada, Naoto Terami, Takashi Hatanaka, Hiromi Tachibana, Atsuko Nakatsuka, Chikage Sato Horiguchi, Naoko Nishii, Hirofumi Makino

PloS one 9 ( 1 ) e85594 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）

Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-γ (PPARγ) and PPARα, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4α, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARδ was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor α in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN.

DOI： 10.1371/journal.pone.0085594

Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. 国際誌

Naoto Terami, Daisuke Ogawa, Hiromi Tachibana, Takashi Hatanaka, Jun Wada, Atsuko Nakatsuka, Jun Eguchi, Chikage Sato Horiguchi, Naoko Nishii, Hiroshi Yamada, Kohji Takei, Hirofumi Makino

PloS one 9 ( 6 ) e100777 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic β-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-β, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, β-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

DOI： 10.1371/journal.pone.0100777

Interferon regulatory factor 4 regulates obesity-induced inflammation through regulation of adipose tissue macrophage polarization. 国際誌

Jun Eguchi, Xingxing Kong, Masafumi Tenta, Xun Wang, Sona Kang, Evan D Rosen

Diabetes 62 ( 10 ) 3394 - 403 2013年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Interferon regulatory factors (IRFs) play functionally diverse roles in the transcriptional regulation of the immune system. We have previously shown that several IRFs are regulators of adipogenesis and that IRF4 is a critical transcriptional regulator of adipocyte lipid handling. However, the functional role of IRF4 in adipose tissue macrophages (ATMs) remains unclear, despite high expression there. Here we show that IRF4 expression is regulated in primary macrophages and in ATMs of high-fat diet-induced obese mice. Irf4(-/-) macrophages produce higher levels of proinflammatory cytokines, including interleukin-1β and tumor necrosis factor-α, in response to fatty acids. In coculture experiments, IRF4 deletion in macrophages leads to reduced insulin signaling and glucose uptake in 3T3-L1 adipocytes. To determine the macrophage-specific function of IRF4 in the context of obesity, we generated myeloid cell-specific IRF4 knockout mice, which develop significant insulin resistance on a high-fat diet, despite no difference in adiposity. This phenotype is associated with increased expression of inflammatory genes and decreased insulin signaling in adipose tissue, skeletal muscle, and liver. Furthermore, Irf4(-/-) ATMs express markers suggestive of enhanced M1 polarization. These findings indicate that IRF4 is a negative regulator of inflammation in diet-induced obesity, in part through regulation of macrophage polarization.

DOI： 10.2337/db12-1327

Phosphatidylethanolamine N-Methyltransferase (PEMT) Deficiency Protects from Obesity and Insulin Resistance but Promote Steatoheptitis With Tumorigenesis

Atsuko Nakatsuka, Jun Wada, Kazutoshi Murakami, Takahiro Terami, Jun Eguchi, Daisuke Ogawa, Hirofumi Makino

DIABETES 62 A529 - A529 2013年7月

Visceral adipose tissue-derived serine proteinase inhibitor inhibits apoptosis of endothelial cells as a ligand for the cell-surface GRP78/voltage-dependent anion channel complex. 国際誌

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

Circulation research 112 ( 5 ) 771 - 80 2013年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

RATIONALE: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. OBJECTIVE: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. METHODS AND RESULTS: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using (125)I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10(-9) m) by the treatment of 5 μM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca(2+) influx and subsequent apoptosis. CONCLUSIONS: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.

DOI： 10.1161/CIRCRESAHA.111.300049

　前のページ - 次のページ　

1
2
3
4
5