慢性腎臓病と心血管病の連関機序の解明と治療法開発

• 研究課題/領域番号: 21591047
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 腎臓内科学
• 研究機関: 川崎医科大学
• 研究代表者: 柏原 直樹 川崎医科大学, 医学部, 教授 (10233701)
• 研究分担者: 冨田 奈留也 (富田 奈留也) 川崎医科大学, 医学部, 准教授 (70314432) ; 佐藤 稔 川崎医科大学, 医学部, 講師 (70449891)
• 研究期間 (年度): 2009 – 2011
• 研究課題ステータス: 完了 (2011年度)
• 配分額: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2011年度: 780千円 (直接経費: 600千円、間接経費: 180千円); 2010年度: 1,820千円 (直接経費: 1,400千円、間接経費: 420千円); 2009年度: 1,950千円 (直接経費: 1,500千円、間接経費: 450千円)
• キーワード: 慢性腎臓病 / アルブミン尿 / 内皮障害 / グライコカリックス / 内皮機能障害 / バイオイメージング / 酸化ストレス / Glycocalyx / 心血管病 / NO

研究概要

アルブミン尿は心血管病と深く関連しており、血管内皮機能障害の反映であると推測されていたが、詳細は不明であった。2光子レ-ザ-顕微鏡を用いて生体腎における微小血流、濾過を可視化検出しうるin vivo live imaging技術を確立した。糖尿病等の病態糸球体では大分子量物質の過剰濾過状態がアルブミン尿出現前より先行出現することが判明し、またこれには内皮機能障害、内皮グライコカリックスの減少の関与が明らかになった。

研究成果

• [雑誌論文] Azelnidipine attenuates glomerular damage in Dahl salt-sensitive rats by suppressing sympathetic nerve activity (2012)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Fujimoto, S, Tomita, N, Sasaki, T & Kashihara, N
  • 雑誌名: Hypertens Res 巻: 35 ページ: 348-55
  • NAID: 10030644635
• [雑誌論文] Endothelial dysfunction promotes the transition from compensatory renal hypertrophy to kidney injury after unilateral nephrectomy in mice (2012)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Kidokoro, K, Nishi, Y, Channon, KM, Sasaki, T & Kashihara, N
  • 雑誌名: Am J Physiol Renal Physiol 巻: 302
• [雑誌論文] Endothelial dysfunction promotes the transition from compensatory renal hypertrophy to kidney injury after unilateral nephrectomy in mice (2012)
  • 著者名/発表者名: Nagasu H
  • 雑誌名: Am J Physiol Renal Physiol 巻: (in press) 号: 11 ページ: F1402-F1408
  • DOI: 10.1152/ajprenal.00459.2011
  • 査読あり
• [雑誌論文] Chronic Kidney Disease, Dyslipidemia, and Atherosclerosis (2012)
  • 著者名/発表者名: Shoji T
  • 雑誌名: Ｊｏｕｒｎａｌ ｏｆ Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ ａｎｄ Ｔｈｒｏｍｂｏｓｉｓ 巻: 19 号: 4 ページ: 299-315
  • DOI: 10.5551/jat.10454
  • NAID: 130004444596
  • ISSN: 1340-3478, 1880-3873
  • 査読あり
• [雑誌論文] Overexpression of klotho protein modulates uninephrectomy-induced compensatory renal hypertrophy by suppressing IGF-I signals (2011)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Kuwabara, A, Yorimitsu, D, Kidokoro, K, Nishi, Y, Tomita, N, Sasaki, T & Kashihara, N
  • 雑誌名: Biochem Biophys Res Commun
• [雑誌論文] Comparison of combination therapy of olmesartan plus azelnidipine or hydrochlorothiazide on renal and vascular damage in SHR/NDmcr-cp rats (2011)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Yorimitsu, D, Tomita, N, Sasaki, T & Kashihara, N
  • 雑誌名: Kidney Blood Press Res 巻: 34 ページ: 87-96
• [雑誌論文] Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney (2011)
  • 著者名/発表者名: Satoh, M, Fujimoto, S, Horike, H, Ozeki, M, Nagasu, H, Tomita, N, Sasaki, T & Kashihara, N
  • 雑誌名: Lab Invest 巻: 91 ページ: 190-202
• [雑誌論文] A Novel Mutation ApoE2 Kurashiki (R158P) in a Patient with Lipoprotein Glomerulopathy (2011)
  • 著者名/発表者名: Tokura T
  • 雑誌名: Ｊｏｕｒｎａｌ ｏｆ Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ ａｎｄ Ｔｈｒｏｍｂｏｓｉｓ 巻: 18 号: 6 ページ: 536-541
  • DOI: 10.5551/jat.8102
  • NAID: 130004444518
  • ISSN: 1340-3478, 1880-3873
  • 査読あり
• [雑誌論文] Overexpression of klotho protein modulates uninephrectomy-induced compensatory renal hypertrophy by suppressing IGF-1 signals. (2011)
  • 著者名/発表者名: Nagasu H, Satoh M, Kuwabara A, Yorimitsu D, Kidokoro K, Nishi Y, Tomita N, Sasaki T, Kashihara N.
  • 雑誌名: Biochem Biophys Res Commun. 巻: 407 ページ: 39-43
  • 査読あり
• [雑誌論文] Comparison of combination therapy of olmesartan plus azelnidipine or hydrochlorothiazide on renal and vascular damage in SHR/NDmcr-cp rats. (2011)
  • 著者名/発表者名: Nagasu H, Satoh M, Yorimitsu D, Tomita N, Sasaki T, Kashihara N.
  • 雑誌名: Kidney Blood Press Res. 巻: 34 ページ: 87-96
  • 査読あり
• [雑誌論文] Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney. (2011)
  • 著者名/発表者名: Satoh M, Fujimoto S, Horike H, Ozeki M, Nagasu H, Tomita N, Sasaki T, Kashihara N.
  • 雑誌名: Lab Invest. 巻: 91 ページ: 190-202
  • 査読あり
• [雑誌論文] Clear Correlation of Tetrahydrobiopterin with Nitric Oxide Bioavailability in Continuous Ambulatory Peritoneal Dialysis (2010)
  • 著者名/発表者名: Mochizuki, S, Takayama, A, Sasaki, T, Yada, T, Endo, K, Horike, H, Kashihara, N, Ogasawara, Y & Kajiya, F
  • 雑誌名: Blood Purif 巻: 30 ページ: 96-97
• [雑誌論文] Renal denervation reduces glomerular injury by suppressing NAD(P) H oxidase activity in Dahl salt-sensitive rats (2010)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Kuwabara, A, Yorimitsu, D, Sakuta, T, Tomita, N & Kashihara, N
  • 雑誌名: Nephrol Dial Transplant
• [雑誌論文] Involvement of the renin-angiotensin system in the development of vascular damage in a rat model of arthritis : effect of angiotensin receptor blockers (2010)
  • 著者名/発表者名: Sakuta, T, Morita, Y, Satoh, M, Fox, DA & Kashihara, N
  • 雑誌名: Arthritis Rheum 巻: 62 ページ: 1319-28
• [雑誌論文] Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney (2010)
  • 著者名/発表者名: Satoh, M, Fujimoto, S, Horike, H, Ozeki, M, Nagasu, H, Tomita, N, Sasaki, T & Kashihara, N
  • 雑誌名: Lab Invest
• [雑誌論文] Oxidative Stress in Diabetic Nephropathy (2010)
  • 著者名/発表者名: Kashihara, N, Haruna, Y, Kondeti, VK & Kanwar, YS
  • 雑誌名: Curr Med Chem 巻: 17(34) ページ: 4256-69
• [雑誌論文] Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats (2010)
  • 著者名/発表者名: Satoh, M, Haruna, Y, Fujimoto, S, Sasaki, T & Kashihara, N
  • 雑誌名: Hypertens Res 巻: 33 ページ: 135-42
  • NAID: 10026126319
• [雑誌論文] Deterioration of glomerular endothelial surface layer induced by oxidative stress is implicated in altered permeability of macromolecules in Zucker fatty rats (2010)
  • 著者名/発表者名: Kuwabara, A, Satoh, M, Tomita, N, Sasaki, T & Kashihara, N
  • 雑誌名: Diabetologia 巻: 53 ページ: 2056-65
• [雑誌論文] In vivo visualization of glomerular microcirculation and hyperfiltration in streptozotocin-induced diabetic rats (2010)
  • 著者名/発表者名: Satoh, M, Kobayashi, S, Kuwabara, A, Tomita, N, Sasaki, T & Kashihara, N
  • 雑誌名: Microcirculation 巻: 17 ページ: 103-12
• [雑誌論文] Erythropoietin Enhances Hydrogen Peroxide-Mediated Dilatation of Canine Coronary Collateral Arterioles during Myocardial Ischemia in Dogs in Vivo (2010)
  • 著者名/発表者名: Yada, T, Shimokawa, H, Hiramatsu, O, Satoh, M, Kashihara, N, Takaki, A, Goto, M, Ogasawara, Y & Kajiya, F
  • 雑誌名: Am J Physiol Heart Circ Physiol
• [雑誌論文] Oxidative stress in diabetic nephropathy. (2010)
  • 著者名/発表者名: Kashihara N, Haruna Y, Kondeti VK, Kanwar YS.
  • 雑誌名: Curr Med Chem. 巻: 17 ページ: 4256-4269
  • 査読あり
• [雑誌論文] Deterioration of glomerular endothelial surface layer induced by oxidative stress is implicated in altered permeability of macromolecules in Zucker fatty rats. (2010)
  • 著者名/発表者名: Kuwabara A, Satoh M, Tomita N, Sasaki T, Kashihara N.
  • 雑誌名: Diabetologia. 巻: 53 ページ: 2056-2065
  • 査読あり
• [雑誌論文] Renal denervation reduces glomerular injury by suppressing NAD(P)H oxidase activity in Dahl salt-sensitive rats. (2010)
  • 著者名/発表者名: Nagasu H, Satoh M, Kuwabara A, Yorimitsu D, Sakuta T, Tomita N, Kashihara N.
  • 雑誌名: Nephrol Dial Transplant. 巻: 25 ページ: 2889-2898
  • 査読あり
• [雑誌論文] Involvement of the renin-angiotensin system in the development of vascular damage in a rat model of arthritis : effect of angiotensin receptor blockers. (2010)
  • 著者名/発表者名: Sakuta T, Morita Y, Satoh M, Fox DA, Kashihara N.
  • 雑誌名: Arthritis Rheum. 巻: 62 ページ: 1319-1328
  • 査読あり
• [雑誌論文] Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats. (2010)
  • 著者名/発表者名: Satoh M, Haruna Y, Fujimoto S, Sasaki T, Kashihara N.
  • 雑誌名: Hypertens Res. 巻: 33 ページ: 135-142
  • NAID: 10026126319
  • 査読あり
• [雑誌論文] Renal denervation reduces glomerular injury by suppressing NAD(P)H oxidase activity in Dahl salt-sensitive rats (2010)
  • 著者名/発表者名: Nagasu H, Satoh M, Kuwabara A, Yorimitsu D, Sakuta T, Tomita N, Kashihara N.
  • 雑誌名: Nephrol Dial Transplant. (印刷中)
  • 査読あり
• [雑誌論文] Involvement of the renin-angiotensin system in the development of vascular damage in a rat arthritis model : Efect of angiotensin receptor blockers (2010)
  • 著者名/発表者名: Sakuta T, Morita Y, Satoh M, Kashihara N, Fox DA
  • 雑誌名: Arthritis Rheum (印刷中)
  • 査読あり
• [雑誌論文] In vivo visualization of glomerular microcirculation and hyper filtration in streptozotocin-induced diabetic rats (2010)
  • 著者名/発表者名: Satoh M, Kobayashi S, Kuwabara A, Tomita N, Sasaki T, Kashihara N.
  • 雑誌名: Microcirculation 17 ページ: 103-112
  • 査読あり
• [雑誌論文] Telmisartan improves endothelial dysfunction and renalautoregulation in Dahl salt sensitive rats (2010)
  • 著者名/発表者名: Satoh M, Haruna Y, Fujimoto S, Sasaki T, Kashihara N.
  • 雑誌名: Hypertens Res 33 ページ: 135-142
  • NAID: 10026126319
  • 査読あり
• [学会発表] Endothelial Cell Interacted with Podocyte and Mesangial Cells Via NAD(P) H Oxidase (2012)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Kidokoro, K, Kashihara, N
  • 学会等名: 49th ERA-EDTA Congress
  • 発表場所: Paris, France
  • 年月日: 2012-05-25
• [学会発表] Preservation of Endothelial GTP Cyclohydrolase I Activity and Improvement of Renal Nitric Oxide Availability Prevent the Development of Diabetic Nephropathy (2012)
  • 著者名/発表者名: Kidkoro, K, Satoh, M, Nagasu, H, Nishi, Y, Ihoriya, C, Kadoya, H, Yada, T, Keith M Channon, Sasaki, T, Kashihara N
  • 学会等名: 49th ERA-EDTA Congress
  • 発表場所: Paris, France
  • 年月日: 2012-05-25
• [学会発表] The Glycocalyx (2011)
  • 著者名/発表者名: Kashihara, N
  • 学会等名: Third International Symposium on Albuminuria
  • 発表場所: Groningen, the Netherlands
  • 年月日: 2011-11-30
• [学会発表] Selective Estrogen Receptor Modulator Inhibits Fatty Acid-Induced Inflammasome Activation and Attenuates Proteinuria-Induced Tubular Injury in Mice (2011)
  • 著者名/発表者名: Nishi Y
  • 学会等名: American Society of Nephrology Kidney Week 2011
  • 発表場所: Philadelphia
  • 年月日: 2011-11-12
• [学会発表] Low-Dose Erythropoietin Increases Superoxide Production in Normal Rat Aorta and Endothelial Cells (2011)
  • 著者名/発表者名: Ihoriya C
  • 学会等名: American Society of Nephrology Kidney Week 2011
  • 発表場所: Philadelphia
  • 年月日: 2011-11-12
• [学会発表] Implications of Oxidative Stress Derived from Endothelial NAD(P) H Oxdase in the Development of Diabetic Nephropathy (2011)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Kuwabara, A, Kidokoro, K, Tomita, N, Sasaki, T, Kashihara, N
  • 学会等名: American Society of Nephrology Kidney Week 2011
  • 発表場所: Philadelphia, USA
  • 年月日: 2011-11-11
• [学会発表] Implications of Oxidative Stress Derived from Endothelial NAD(P)H Oxdase in the Development of Diabetic Nephropathy (2011)
  • 著者名/発表者名: Nagasu H
  • 学会等名: American Society of Nephrology Kidney Week 2011
  • 発表場所: Philadelphia
  • 年月日: 2011-11-11
• [学会発表] Mouse Renal Fibrosis after Unilateral Ureteral Obstruction Is Reduced by Klotho Protein Overexpression through Wnt Signaling Inhibition (2011)
  • 著者名/発表者名: Satoh M
  • 学会等名: American Society of Nephrology Kidney Week 2011
  • 発表場所: Philadelphia
  • 年月日: 2011-11-10
• [学会発表] Preservation of Endothelial GTP Cyclohydrolase I Activity by Metformin Prevent the Development of Diabetic Nephropathy (2011)
  • 著者名/発表者名: Kidokoro K
  • 学会等名: American Society of Nephrology Kidney Week 2011
  • 発表場所: Philadelphia
  • 年月日: 2011-11-10
• [学会発表] Endothelial NAD(P)H oxidase activation enhance urinary albumin excretion and progress renal dysfunction in mouse type 1 diabetic nephropathy (2011)
  • 著者名/発表者名: Nagasu H
  • 学会等名: International Society of Nephrology (ISN)
  • 発表場所: Aarhus, Denmark
  • 年月日: 2011-09-22
• [学会発表] Role of GTP cyclohydrolase-1 as a novel therapeutic target of diabetic nephropathy (2011)
  • 著者名/発表者名: Kidokoro K
  • 学会等名: International Society of Nephrology (ISN)
  • 発表場所: Aarhus, Denmark
  • 年月日: 2011-09-22
• [学会発表] Selective Estrogen Receptor Modulator Ameriorate Proteinuria Induced Tubular Damage by Reducing Oxidative Mitochondrial Stress (2011)
  • 著者名/発表者名: Nishi Y
  • 学会等名: WCN 2011世界腎臓学会議/World Congress of Nephrology
  • 発表場所: Vancouver, Canada
  • 年月日: 2011-04-11
• [学会発表] Cyclic GMP Dependent Protein Kinase-Akt Pathway is Essential for Compensatory Renal Hypertrophy and Maintenance Renal Function After Unilateral Nephrectomy (2011)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Kidokoro, K, Tomita, N, Sasaki, T, Kashihara, N
  • 学会等名: World Congress of N ephrology 2011
  • 発表場所: Vancouver, Canada
  • 年月日: 2011-04-10
• [学会発表] Cyclic GMP Dependent Protein Kinase-Akt Pathway is Essential for Compensatory Renal Hypertrophy and Maintenance Renal Function After Unilateral Nephrectomy (2011)
  • 著者名/発表者名: Nagasu H
  • 学会等名: WCN 2011世界腎臓学会議/World Congress of Nephrology
  • 発表場所: Vancouver, Canada
  • 年月日: 2011-04-10
• [学会発表] Over-Expression of Endothelial GTP Cyclohydrolase-Ameliorates Mouse Diabetic Glomerulopathy (2011)
  • 著者名/発表者名: Kidokoro K
  • 学会等名: WCN 2011世界腎臓学会議/World Congress of Nephrology
  • 発表場所: Vancouver, Canada
  • 年月日: 2011-04-10
• [学会発表] Erythropoiesis-Stimulating Agent Aggravates Vascular Endothelial Function in Normal and Chronic renal Failure Rats (2011)
  • 著者名/発表者名: Ihoriya C
  • 学会等名: WCN 2011世界腎臓学会議/World Congress of Nephrology
  • 発表場所: Vancouver, Canada
  • 年月日: 2011-04-10
• [学会発表] Selective Estrogen Receptor Modulator Attenuates Alubumin-Induced Apoptosis in Renal Proximal Tubules through Inhibition ob Mitochondrial Stress. (2010)
  • 著者名/発表者名: Nishi Y, Satoh M, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: American Society of Nephrology Renal Week 2010
  • 発表場所: Denver Colorado
  • 年月日: 2010-11-20
• [学会発表] Nitric Oxide Induces Tubular Cell Hypertrophy Via Cyclic GMP-Dependedent Protein Kinase in Rat Compensatory Renal Hypertrophy (2010)
  • 著者名/発表者名: Nagasu, H, Satoh, M, Tomita, N, Sasaki, T, Kashihara, N
  • 学会等名: American Society of Nephrology Renal Week 2010
  • 発表場所: Denver, USA
  • 年月日: 2010-11-19
• [学会発表] Nitric Oxide Induces Tubular Cell Hypertrophy Via Cyclic GMP-Dependedent Protein Kinase in Rat Compensatory Renal Hypertrophy. (2010)
  • 著者名/発表者名: Nagasu H, Satoh M, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: American Society of Nephrology Renal Week 2010
  • 発表場所: Denver Colorado
  • 年月日: 2010-11-19
• [学会発表] Over-Expression of GTP Cyclohydrolase-I Retards Development of Albuminuria and Ameliorates Renal Injuries in Diabetes. (2010)
  • 著者名/発表者名: Kidokoro K, Satoh M, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: American Society of Nephrology Renal Week 2010
  • 発表場所: Denver Colorado
  • 年月日: 2010-11-18
• [学会発表] Mechanisms of acute tacrolims-induced nephrotoxicity and the renoprotective effects of telmisartan. (2010)
  • 著者名/発表者名: Kidokoro K, Nagasu H, Satoh M, Nishi Y, Yorimitsu D, Kuwabara A, Sakuta T, Komai N, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: XLVII ERA-EDTA Congress 2010
  • 発表場所: Munich, Germany
  • 年月日: 2010-06-27
• [学会発表] Renal denervation reduces glomerular superoxide production and protects from gromerular injury in Dahl salt-sensitive rats. (2010)
  • 著者名/発表者名: Nagasu H, Satoh M, Kidokoro K, Nishi Y, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: XLVII ERA-EDTA Congress 2010
  • 発表場所: Munich, Germany
  • 年月日: 2010-06-26
• [学会発表] Calcium channel blokers azelnidipine but not amlodipine reduce glomerular damages in Dahl salt -sansitive rats by suppression of sympathetic nerve system. (2010)
  • 著者名/発表者名: Nishi Y, Satoh M, Nagasu H, Kuwabara A, Yorimitsu D, Kidokoro K, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: XLVII ERA-EDTA Congress 2010
  • 発表場所: Munich, Germany
  • 年月日: 2010-06-26
• [学会発表] Glomerular endothelial glycocalyx was decreases by reactive oxygen species in Zucker obese fatty rat. (2010)
  • 著者名/発表者名: Kuwabara A, Satoh M, Kidokoro K, Nishi Y, Nagasu H, Yorimitsu D, Sakuta T, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: 国際腎臓学会(ISN)NEXUS
  • 発表場所: 京都市
  • 年月日: 2010-04-17
• [学会発表] Renal denervation protects from glomerular injyury by suppressing NAD(P)H oxidase activity in Dahl salt-sensitive rats. (2010)
  • 著者名/発表者名: Nagasu H, Satoh M, Kuwabara A, Sakuta T, Yorimitsu D, Namikoshi T, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: 国際腎臓学会(ISN)NEXUS
  • 発表場所: 京都市
  • 年月日: 2010-04-16
• [学会発表] ARB/CCB combination therapy suppressed oxidative stress compared with ARB/HCTZ combination therapy in glomeruli and aorta of metabolic syndromemodel rats. (2010)
  • 著者名/発表者名: Kidokoro K, Nagasu H, Satoh M, Kuwabara A, Sakuta T, Yorimitsu D, Nishi Y, Tomita N, Sasaki T, Kashihara N.
  • 学会等名: 国際腎臓学会(ISN)NEXUS
  • 発表場所: 京都市
  • 年月日: 2010-04-16
• [学会発表] 糸球体血管内皮透過性制御における内皮細胞 Glycocalyx の役制 (2009)
  • 著者名/発表者名: 桑原篤憲, 佐藤稔, 城所研吾, 西佑子, 依光大祐, 長洲一, 作田建夫, 小林伸哉, 駒井則夫, 冨田奈留也, 佐々木環, 柏原直樹
  • 学会等名: 第32回日本高血圧学会総会
  • 発表場所: 大津プリンスホテル(大津市)
  • 年月日: 2009-10-03
• [学会発表] Dahl食塩感受性ラットに対する腎神経切除による腎保護作用の検討 (2009)
  • 著者名/発表者名: 長洲一, 佐藤稔, 桑原篤憲, 作田建夫, 依光大祐, 浪越為八, 冨田奈留也, 佐々木環, 柏原直樹
  • 学会等名: 第32回日本高血圧学会総会
  • 発表場所: 大津プリンスホテル(大津市)
  • 年月日: 2009-10-03