研究者詳細 - 田邊　克幸

論文 - 田邊　克幸

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An angiotensin II type 1 receptor binding molecule has a critical role in hypertension in a chronic kidney disease model 査読

Ryu Kobayashi, Hiromichi Wakui, Kengo Azushima, Kazushi Uneda, Sona Haku, Kohji Ohki, Kotaro Haruhara, Sho Kinguchi, Miyuki Matsuda, Masato Ohsawa, Yoshiyuki Toya, Akira Nishiyama, Akio Yamashita, Katsuyuki Tanabe, Yohei Maeshima, Satoshi Umemura, Kouichi Tamura

KIDNEY INTERNATIONAL 91 ( 5 ) 1115 - 1125 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Angiotensin II type 1 receptor-associated protein (ATRAP) promotes AT1R internalization along with suppression of hyperactivation of tissue AT1R signaling. Here, we provide evidence that renal ATRAP plays a critical role in suppressing hypertension in a mouse remnant kidney model of chronic kidney disease. The effect of 5/6 nephrectomy on endogenous ATRAP expression was examined in the kidney of C57BL/6 and 129/Sv mice. While 129/Sv mice with a remnant kidney showed decreased renal ATRAP expression and developed hypertension, C57BL/6 mice exhibited increased renal ATRAP expression and resistance to progressive hypertension. Consequently, we hypothesized that downregulation of renal ATRAP expression is involved in pathogenesis of hypertension in the remnant kidney model of chronic kidney disease. Interestingly, 5/6 nephrectomy in ATRAP-knockout mice on the hypertension resistant C57BL/6 background caused hypertension with increased plasma volume. Moreover, in knockout compared to wild-type C57BL/6 mice after 5/6 nephrectomy, renal expression of the epithelial sodium channel cc-subunit and tumor necrosis factor-alpha was significantly enhanced, concomitant with increased plasma membrane angiotensin II type 1 receptor in the kidneys. Thus, renal ATRAP downregulation is involved in the onset and progression of blood pressure elevation caused by renal mass reduction, and implicates ATRAP as a therapeutic target for hypertension in chronic kidney disease.

DOI： 10.1016/j.kint.2016.10.035

Sustained Tubulointerstitial Inflammation in Kidney with Severe Leptospirosis 査読

Keiko Tanaka, Katsuyuki Tanabe, Naoko Nishii, Keiichi Takiue, Hitoshi Sugiyama, Jun Wada

INTERNAL MEDICINE 56 ( 10 ) 1179 - 1184 2017年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAPAN SOC INTERNAL MEDICINE

Leptospirosis is frequently associated with acute kidney injury. Some survivors are known to progress to chronic kidney disease due to sustained tubulointerstitial inflammation. We present a case of severe leptospirosis with acute renal failure. Although antibiotic therapy resolved the infection, moderate renal dysfunction remained. A renal biopsy demonstrated marked inflammatory infiltration in the tubules and interstitium. Many of the inflammatory cells were CD68-positive monocytes/macrophages, predominantly M1 phenotype. An intermediate dose of oral corticosteroids normalized the patient's serum creatinine levels. We suggest that corticosteroid therapy may be a therapeutic option for some patients with sustained tubulointerstitial nephritis who survive severe leptospirosis.

DOI： 10.2169/internalmedicine.56.8084

Antiangiogenic Therapy for Diabetic Nephropathy 査読

Katsuyuki Tanabe, Yohei Maeshima, Yasufumi Sato, Jun Wada

BIOMED RESEARCH INTERNATIONAL 2017 5724069 2017年

担当区分：筆頭著者,　責任著者記述言語：英語出版者・発行元：HINDAWI LTD

Angiogenesis has been shown to be a potential therapeutic target for early stages of diabetic nephropathy in a number of animal experiments. Vascular endothelial growth factor (VEGF) is the main mediator for abnormal angiogenesis in diabetic glomeruli. Although beneficial effects of anti-VEGF antibodies have previously been demonstrated in diabetic animal experiments, recent basic and clinical evidence has revealed that the blockade of VEGF signaling resulted in proteinuria and renal thrombotic microangiopathy, suggesting the importance of maintaining normal levels of VEGF in the kidneys. Therefore, antiangiogenic therapy for diabetic nephropathy should eliminate excessive glomerular angiogenic response without accelerating endothelial injury. Some endogenous antiangiogenic factors such as endostatin and tumstatin inhibit overactivation of endothelial cells but do not specifically block VEGF signaling. In addition, the novel endothelium-derived antiangiogenic factor vasohibin-1 enhances stress tolerance and survival of the endothelial cells, while inhibiting excess angiogenesis. These factors have been demonstrated to suppress albuminuria and glomerular alterations in a diabetic mouse model. Thus, antiangiogenic therapy with promising candidates will possibly improve renal prognosis in patients with early stages of diabetic nephropathy.

DOI： 10.1155/2017/5724069

The Efficacy of Rituximab in High-risk Renal Transplant Recipients 査読

Motoo Araki, Koichiro Wada, Yosuke Mitsui, Risa Kubota, Takashi Yoshioka, Yuichi Ariyoshi, Yasuyuki Kobayashi, Masashi Kitagawa, Katsuyuki Tanabe, Hiroshi Sugiyama, Jun Wada, Masami Watanabe, Toyohiko Watanabe, Katsuyuki Hotta, Yasutomo Nasu

ACTA MEDICA OKAYAMA 70 ( 4 ) 295 - 297 2016年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

Although graft survival following renal transplantation (RTx) has improved, outcomes following highrisk RTx are variable. Preexisting antibodies, including donor-specific antibodies (DSA), play an important role in graft dysfunction and survival. We have designed a study to investigate the safety and efficacy of anti-CD20 monoclonal antibodies (rituximab) in high-risk RTx recipients. Major eligibility criteria include: 1) major and minor ABO blood group mismatch, 2) positive DSA. Thirty-five patients will receive 200 mg/body of rituximab. The primary endpoint is the incidence of B cell depletion. This study will clarify whether rituximab is efficacious in improving graft survival in high-risk RTx recipients.

DOI： 10.18926/AMO/54507

長期透析患者に対する腎移植症例の検討査読

有吉勇一, 荒木元朗, 光井洋介, 吉岡貴史, 和田耕一郎, 小林泰之, 江原伸, 渡邉豊彦, 那須保友, 山下里美, 北川正史, 田邊克幸, 森永裕士, 杉山斉, 和田淳

日本臨床腎移植学会雑誌 4 ( 1 ) 113 - 117 2016年7月

The urinary levels of prostanoid metabolites predict acute kidney injury in heterogeneous adult Japanese ICU patients: a prospective observational study 査読

Haruyo Ujike-Omori, Yohei Maeshima, Masaru Kinomura, Katsuyuki Tanabe, Kiyoshi Mori, Hiroyuki Watatani, Norikazu Hinamoto, Hitoshi Sugiyama, Yoshiki Sakai, Hiroshi Morimatsu, Hirofumi Makino

CLINICAL AND EXPERIMENTAL NEPHROLOGY 19 ( 6 ) 1024 - 1036 2015年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：SPRINGER

Background Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients.
Methods The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the urinary levels of prostaglandin E-2 (PGE(2)), PGI(2) metabolite (2,3-dinor-6-OXO-PGF(1 alpha)), thromboxane A(2) (TXA(2)) metabolite (11-dehydro-TXB2) were determined.
Results Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6-OXO-PGF(1 alpha)/Cr (r = 0.57, p < 0.0001) and 11-dehydro-TXB2/Cr (r = 0.47, p < 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF(1 alpha)/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE(2)/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF(1 alpha)/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC-area under the curve (AUC): 0.75].
Conclusions Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF(1 alpha)/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients.

DOI： 10.1007/s10157-015-1092-4

ONO-1301, a Sustained-Release Prostacyclin Analog, Ameliorates the Renal Alterations in a Mouse Type 2 Diabetes Model Possibly Through Its Protective Effects on Mesangial Cells 査読

Hiroyuki Watatani, Hiroko Yamasaki, Yohei Maeshima, Tatsuyo Nasu, Norikazu Hinamoto, Haruyo Ujike, Hitoshi Sugiyama, Yoshiki Sakai, Katsuyuki Tanabe, Hirofumi Makino

ACTA MEDICA OKAYAMA 69 ( 1 ) 1 - 15 2015年2月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：OKAYAMA UNIV MED SCHOOL

Diabetic nephropathy is the most common pathological disorder predisposing patients to end-stage renal disease. Considering the increasing prevalence of type 2 diabetes mellitus worldwide, novel therapeutic approaches are urgently needed. ONO-1301 is a novel sustained-release prostacyclin analog that inhibits thromboxane A(2) synthase. Here we examined the therapeutic effects of the intermittent administration of slow-release ONO-1301 (SR-ONO) on diabetic nephropathy in obese type 2 diabetes mice, as well as its direct effects on mesangial cells. The subcutaneous injection of SR-ONO (3mg/kg) every 3 wks did not affect the obesity or hyperglycemia in the db/db obese mice used as a model of type 2 diabetes, but it significantly ameliorated their albuminuria, glomerular hypertrophy, glomerular accumulation of type IV collagen, and monocyte/macrophage infiltration, and also the increase of TGF-beta 1, a-smooth muscle actin (alpha-SMA) and MCP-1 compared to vehicle treatment. In cultured mouse mesangial cells, ONO-1301 concentration-dependently suppressed the increases in TGF-beta, type IV collagen, alpha-SMA, MCP-1 and fibronectin induced by high ambient glucose, at least partly through prostacyclin (PGI(2)) receptor-mediated signaling. Taken together, these results suggest the potential therapeutic efficacy of the intermittent administration of SR-ONO against type 2 diabetic nephropathy, possibly through protective effects on mesangial cells.

DOI： 10.18926/AMO/53117

Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy 査読

Miguel A. Lanaspa, Takuji Ishimoto, Christina Cicerchi, Yoshifuru Tamura, Carlos A. Roncal-Jimenez, Wei Chen, Katsuyuki Tanabe, Ana Andres-Hernando, David J. Orlicky, Esteban Finol, Shinichiro Inaba, Nanxing Li, Christopher J. Rivard, Tomoki Kosugi, Laura G. Sanchez-Lozada, J. Mark Petrash, Yuri Y. Sautin, A. Ahsan Ejaz, Wataru Kitagawa, Gabriela E. Garcia, David T. Bonthron, Aruna Asipu, Christine P. Diggle, Bernardo Rodriguez-Iturbe, Takahiko Nakagawa, Richard J. Johnson

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 25 ( 11 ) 2526 - 2538 2014年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER SOC NEPHROLOGY

Diabetes is associated with activation of the polyol pathway, in which glucose is converted to sorbitol by aldose reductase. Previous studies focused on the role of sorbitol in mediating diabetic complications. However, in the proximal tubule, sorbitol can be converted to fructose, which is then metabolized largely by fructokinase, also known as ketohexokinase, leading to ATP depletion, proinflammatory cytokine expression, and oxidative stress. We and others recently identified a potential deleterious role of dietary fructose in the generation of tubulointerstitial injury and the acceleration of CKD. In this study, we investigated the potential role of endogenous fructose production, as opposed to dietary fructose, and its metabolism through fructokinase in the development of diabetic nephropathy. Wild-type mice with streptozotocin-induced diabetes developed proteinuria, reduced GFR, and renal glomerular and proximal tubular injury. Increased renal expression of aldose reductase; elevated levels of renal sorbitol, fructose, and uric acid; and low levels of ATP confirmed activation of the fructokinase pathway. Furthermore, renal expression of inflammatory cytokines with macrophage infiltration was prominent. In contrast, diabetic fructokinase-deficient mice demonstrated significantly less proteinuria, renal dysfunction, renal injury, and inflammation. These studies identify fructokinase as a novel mediator of diabetic nephropathy and document a novel role for endogenous fructose production, or fructoneogenesis, in driving renal disease.

DOI： 10.1681/ASN.2013080901

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1 査読

Norikazu Hinamoto, Yohei Maeshima, Hiroko Yamasaki, Tatsuyo Nasu, Daisuke Saito, Hiroyuki Watatani, Haruyo Ujike, Katsuyuki Tanabe, Kana Masuda, Yuka Arata, Hitoshi Sugiyama, Yasufumi Sato, Hirofumi Makino

PLOS ONE 9 ( 9 ) e107934 2014年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocininduced type 1 diabetic VASH1 heterozygous knockout mice (VASH1(+/-)) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1(+/-) mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-kappa B p65 were significantly exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of I kappa B alpha, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31(+) endothelial area was also increased in the diabetic VASH1(+/-) mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-beta(1)/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1(+/-) mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the development of diabetic renal alterations, partly via direct effects on podocytes, and thus, a strategy to recover VASH1 might potentially lead to the development of a novel therapeutic approach for diabetic nephropathy.

DOI： 10.1371/journal.pone.0107934

Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids 査読

Christina Cicerchi, Nanxing Li, James Kratzer, Gabriela Garcia, Carlos A. Roncal-Jimenez, Katsuyuki Tanabe, Brandi Hunter, Christopher J. Rivard, Yuri Y. Sautin, Eric A. Gaucher, Richard J. Johnson, Miguel A. Lanaspa

FASEB JOURNAL 28 ( 8 ) 3339 - 3350 2014年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：FEDERATION AMER SOC EXP BIOL

Reduced AMP kinase (AMPK) activity has been shown to play a key deleterious role in increased hepatic gluconeogenesis in diabetes, but the mechanism whereby this occurs remains unclear. In this article, we document that another AMP-dependent enzyme, AMP deaminase (AMPD) is activated in the liver of diabetic mice, which parallels with a significant reduction in AMPK activity and a significant increase in intracellular glucose accumulation in human HepG2 cells. AMPD activation is induced by a reduction in intracellular phosphate levels, which is characteristic of insulin resistance and diabetic states. Increased gluconeogenesis is mediated by reduced TORC2 phosphorylation at Ser171 by AMPK in these cells, as well as by the up-regulation of the rate-limiting enzymes PEPCK and G6Pc. The mechanism whereby AMPD controls AMPK activation depends on the production of a specific AMP downstream metabolite through AMPD, uric acid. In this regard, humans have higher uric acid levels than most mammals due to a mutation in uricase, the enzyme involved in uric acid degradation in most mammals, that developed during a period of famine in Europe 1.5 x 10(7) yr ago. Here, working with resurrected ancestral uricases obtained from early hominids, we show that their expression on HepG2 cells is enough to blunt gluconeogenesis in parallel with an up-regulation of AMPK activity. These studies identify a key role AMPD and uric acid in mediating hepatic gluconeogenesis in the diabetic state, via a mechanism involving AMPK down-regulation and overexpression of PEPCK and G6Pc. The uricase mutation in the Miocene likely provided a survival advantage to help maintain glucose levels under condi-tions of near starvation, but today likely has a role in the pathogenesis of diabetes.

DOI： 10.1096/fj.13-243634

Urinary and Plasma Levels of Vasohibin-1 Can Predict Renal Functional Deterioration in Patients with Renal Disorders 査読

Norikazu Hinamoto, Yohei Maeshima, Daisuke Saito, Hiroko Yamasaki, Katsuyuki Tanabe, Tatsuyo Nasu, Hiroyuki Watatani, Haruyo Ujike, Masaru Kinomura, Hitoshi Sugiyama, Hikaru Sonoda, Yasufumi Sato, Hirofumi Makino

PLOS ONE 9 ( 6 ) e96932 2014年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PUBLIC LIBRARY SCIENCE

Vasohibin-1 (VASH-1) is a negative feedback regulator of angiogenesis, and a small vasohibin-binding protein (SVBP) serves as its secretory chaperone and contributes to its antiangiogenic effects. In the present study, we aimed to define the clinical significance of VASH-1 and SVBP in patients with chronic kidney disease (CKD). We recruited 67 Japanese hospitalized patients with renal disorders with (n = 45) or without (n = 22) renal biopsy samples and 10 Japanese healthy controls. We evaluated the correlations between the plasma and urinary levels of VASH-1/VASH-1-SVBP complex/SVBP and the clinicopathological parameters. The plasma levels of VASH-1 were inversely correlated with age and systolic and diastolic blood pressure and positively correlated with crescent formation. Increased plasma and urinary levels of VASH-1 and VASH-1-SVBP complex were significantly correlated with worse renal outcomes. These results demonstrate an association between elevated urinary and plasma levels of VASH-1 and progressive decline of the renal function, thus suggesting a potential role for VASH-1 in predicting a worse renal prognosis in patients with renal disease, including CKD.

DOI： 10.1371/journal.pone.0096932

Renal distribution of Vasohibin-1 in patients with chronic kidney disease 査読

Norikazu Hinamoto, Yohei Maeshima, Daisuke Saito, Hiroko Yamasakr, Katsuyuki Tanabe, Tatsuyo Nasu, Hiroyuki Watatani, Haruyo Ujike, Masaru Kinomura, Hitoshi Sugiyama, Hikaru Sonoda, Naoki Kanomata, Yasufumi Sate, Hirofumi Makino

Acta Medica Okayama 68 ( 4 ) 219 - 233 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Okayama University

Experimental studies have demonstrated the involvement of angiogenesis-related factors in the progression of chronic kidney disease (CKD). There have so far been no reports investigating the distribution and clinical roles of Vasohibin-1 (VASH-1), a negative feedback regulator of angiogenesis, in CKD. We recruited 54 Japanese CKD patients and 6 patients who had normal renal tissues excised due to localized renal cell carcinoma. We evaluated the correlations between the renal expression level of VASH-1 and the clinical/histological parameters. VASH-1 was observed in renal endothelial/mesangial cells, crescentic lesions and interstitial inflammatory cells. Significant positive correlations were observed between 1) crescent formation and the number of VASH-1+ cells in the glomerulus (r=0.48, /&gt
= 0.001) or cortex (r = 0.64, p&lt
0.0001), 2) interstitial cell infiltration and the number of VASH-1+ cells in the cortex (r = 0.34, p = 0.02), 3) the glomerular VEGFR-2+ area and the number of VASH 1+ cells in the glomerulus (r = 0.44, p = 0.01) or medulla (r = 0.63, p = 0.01). These results suggest that the renal levels of VASH-1 may be affected by local inflammation, crescentic lesions and VEGFR-2. © 2014 by Okayama University Medical School.

DOI： 10.18926/AMO/52788

Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction 査読

Hiroyuki Watatani, Yohei Maeshima, Norikazu Hinamoto, Hiroko Yamasaki, Haruyo Ujike, Katsuyuki Tanabe, Hitoshi Sugiyama, Fumio Otsuka, Yasufumi Sato, Hirofumi Makino

Physiological Reports 2 ( 6 ) 2014年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：American Physiological Society

Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease (CKD). We recently reported the protective role of Vasohibin-1(VASH-1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH-1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin-1 heterozygous knockout mice (VASH-1+/-) or wild-type (WT) (VASH-1+/+) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys (OBK) were significantly exacerbated in VASH-1+/- mice compared with WT mice (Day 7). The increases in the renal levels of TGF-β1, pSmad3, NF-jB pp65, CCL2 mRNA, and the number of interstitial fibroblast-specific protein-1 (FSP-1)+ fibroblasts in the OBK were significantly aggravated in VASH-1+/- mice. In addition, treatment with VASH-1 siRNA enhanced the TGF-β1-induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH-1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti-fibrotic effects of VASH-1 on renal fibroblasts through its modulation of TGF-β1 signaling.

DOI： 10.14814/phy2.12054

Umami: The Taste That Drives Purine Intake 査読

Richard J. Johnson, Takahiko Nakagawa, L. Gabriela Sanchez-Lozada, Miguel A. Lanaspa, Yoshifuru Tamura, Katsuyuki Tanabe, Takuji Ishimoto, Jeffrey Thomas, Shinichiro Inaba, Wataru Kitagawa, Christopher J. Rivard

JOURNAL OF RHEUMATOLOGY 40 ( 11 ) 1794 - 1796 2013年11月

Epicatechin limits renal injury by mitochondrial protection in cisplatin nephropathy 査読

Katsuyuki Tanabe, Yoshifuru Tamura, Miguel A. Lanaspa, Makoto Miyazaki, Norihiko Suzuki, Waichi Sato, Yohei Maeshima, George F. Schreiner, Francisco J. Villarreal, Richard J. Johnson, Takahiko Nakagawa

American Journal of Physiology - Renal Physiology 303 ( 9 ) F1264 - F1274 2012年11月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

Cisplatin nephropathy can be regarded as a mitochondrial disease. Intervention to halt such deleterious injury is under investigation. Recently, the flavanol (-)-epicatechin emerges as a novel compound to protect the cardiovascular system, owing in part to mitochondrial protection. Here, we have hypothesized that epicatechin prevents the progression of cisplatininduced kidney injury by protecting mitochondria. Epicatechin was administered 8 h after cisplatin injury was induced in the mouse kidney. Cisplatin significantly induced renal dysfunction and tubular injury along with an increase in oxidative stress. Mitochondrial damages were also evident as a decrease in loss of mitochondrial mass with a reduction in the oxidative phosphorylation complexes and low levels of MnSOD. The renal damages and mitochondrial injuries were significantly prevented by epicatechin treatment. Consistent with these observations, an in vitro study using cultured mouse proximal tubular cells demonstrated that cisplatin-induced mitochondrial injury, as revealed by a decrease in mitochondrial succinate dehydrogenase activity, an induction of cytochrome c release, mitochondrial fragmentation, and a reduction in complex IV protein, was prevented by epicatechin. Such a protective effect of epicatechin might be attributed to decreased oxidative stress and reduced ERK activity. Finally, we confirmed that epicatechin did not perturb the anticancer effect of cisplatin in HeLa cells. In conclusion, epicatechin exhibits protective effects due in part to its ability to prevent the progression of mitochondrial injury in mouse cisplatin nephropathy. Epicatechin may be a novel option to treat renal disorders associated with mitochondrial dysfunction. © 2012 the American Physiological Society.

DOI： 10.1152/ajprenal.00227.2012

Nicorandil, a K atp channel opener, alleviates chronic renal injury by targeting podocytes and macrophages 査読

Yoshifuru Tamura, Katsuyuki Tanabe, Wataru Kitagawa, Shunya Uchida, George F. Schreiner, Richard J. Johnson, Takahiko Nakagawa

American Journal of Physiology - Renal Physiology 303 ( 3 ) F339 - F349 2012年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Nicorandil exhibits a protective effect in the vascular system, which is thought to be due to vasodilatation from opening ATP-dependent potassium channels and donation of nitric oxide. Recently, nicorandil was shown to be renoprotective in models of acute kidney injury and glomerulone-phritis. However, the specific mechanisms of renoprotection are unclear. We evaluated the effect of nicorandil on the rat remnant kidney model of chronic kidney disease. Blood pressure was unchanged by a 10-wk course of nicorandil, while albuminuria was significantly reduced. Glomerular injury and tubulointerstitial injury were also ameliorated by nicorandil. Oxidative stress, as noted by renal nitrotyrosine level and urine 8-hydroxy-2′-deoxyguanosine, were elevated in this model and was significantly reduced by nic-orandil treatment. Treatment was associated with maintenance of the mitochondrial antioxidant, manganese SOD, in podocytes and with suppression of xanthine oxidase expression in infiltrating macro-phages. Interestingly, these two cell types express sulfonylurea receptor 2 (SUR2), a binding site of nicorandil in the ATP-dependent K channel. Consistently, we found that stimulating SUR2 with nic-orandil prevented angiotensin II-mediated upregulation of xanthine oxidase in the cultured macrophage, while xanthine oxidase expression was rather induced by blocking SUR2 with glibenclamide. In conclusion, nicorandil reduces albuminuria and ameliorates renal injury by blocking oxidative stress in chronic kidney disease. © 2012 the American Physiological Society.

DOI： 10.1152/ajprenal.00158.2012

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

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

記述言語：英語掲載種別：研究論文（学術雑誌）

Tubulointerstitial 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-β 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 α-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-β1 as detected by immunoblot and immunocytochemistry, partly dependent on PGI2 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-β. © 2012 the American Physiological Society.

DOI： 10.1152/ajprenal.00538.2011

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

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 - F1161 2012年5月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

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. © 2012 the American Physiological Society.

DOI： 10.1152/ajprenal.00596.2011

Sucrose induces fatty liver and pancreatic inflammation in male breeder rats independent of excess energy intake 査読

Carlos A. Roncal-Jimenez, Miguel A. Lanaspa, Christopher J. Rivard, Takahiko Nakagawa, L. Gabriela Sanchez-Lozada, Diana Jalal, Ana Andres-Hernando, Katsuyuki Tanabe, Magdalena Madero, Nanxing Li, Christina Cicerchi, Kim Mc Fann, Yuri Y. Sautin, Richard J. Johnson

METABOLISM-CLINICAL AND EXPERIMENTAL 60 ( 9 ) 1259 - 1270 2011年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：W B SAUNDERS CO-ELSEVIER INC

Fructose induces metabolic syndrome in rats; but studies have been criticized for using high concentrations of fructose that are not physiologic, for using only pure fructose, and for not controlling for energy intake. We tested the hypothesis that a 40% sucrose diet (containing 20% fructose) might induce features of metabolic syndrome in male breeder rats independent of excess energy intake. Male Sprague-Dawley breeder rats were pair fed 40% sucrose or isocaloric starch diet for 4 months and evaluated for metabolic syndrome and diabetes. In vitro studies were performed in rat insulinoma cells (RIN-m5F) exposed to uric acid, and markers of inflammation were assessed. Rats fed a 40% sucrose diet developed accelerated features of metabolic syndrome with up-regulation of fructose-dependent transporter Glut5 and fructokinase. Fatty liver and low-grade pancreatic inflammation also occurred. Uric acid was found to stimulate inflammatory mediators and oxidative stress in islet cells in vitro. Sucrose, at concentrations ingested by a subset of Americans, can accelerate metabolic syndrome, fatty liver, and type 2 diabetes mellitus in male breeder rats; and the effects are independent of excess energy intake. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.metabol.2011.01.008

Selective Stimulation of VEGFR2 Accelerates Progressive Renal Disease 査読

Waichi Sato, Katsuyuki Tanabe, Tomoki Kosugi, Kelly Hudkins, Miguel A. Lanaspa, Li Zhang, Martha Campbell-Thompson, Qiuhong Li, David A. Long, Charles E. Alpers, Takahiko Nakagawa

AMERICAN JOURNAL OF PATHOLOGY 179 ( 1 ) 155 - 166 2011年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：ELSEVIER SCIENCE INC

Vascular endothelial growth factor A (VEGF-A) can play both beneficial and deleterious roles in renal diseases, where its specific function might be determined by nitric oxide bioavailability. The complexity of VEGF-A in renal disease could in part be accounted for by the distinct roles of its two receptors; VEGFR1 is involved in the inflammatory responses, whereas VEGFR2 predominantly mediates angiogenesis. Because nondiabetic chronic renal disease is associated with capillary loss, we hypothesized that selective stimulation of VEGFR2 could be beneficial in this setting. However, VEGFR2 activation may be deleterious in the presence of nitric oxide deficiency. We systematically overexpressed a mutant form of VEGF-A binding only VEGFR2 (Flk-sel) using an adeno-associated virus-1 vector in wild-type and eNOS knockout mice and then induced renal injury by uninephrectomy. Flksel treatment increased angiogenesis and lowered blood pressure in both mouse types. Flk-set overexpression caused mesangial injury with increased proliferation associated with elevated expression of PDGF, PDGF-beta receptor, and VEGFR2; this effect was greater in eNOS knockout than in wild-type mice. Flk-sel also induced tubulointerstitial injury, with some tubular epithelial cells expressing alpha-smooth muscle actin, indicating a phenotypic evolution toward myofibroblasts. In conclusion, prestimulation of VEGFR2 can potentiate subsequent renal injury in mice, an effect enhanced in the setting of nitric oxide deficiency. Pathol 2011, 179: 155-166. DOI: 10.1016/j.ajpath.2011.03.024)

DOI： 10.1016/j.ajpath.2011.03.024

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