慢性腎臓病と心血管病の連関機序としてのアルブミン尿出現の分子機序の解明

2013 年度 研究成果報告書

• 研究課題/領域番号: 23591209
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 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: 駒井 則夫 川崎医科大学, 医学部, 准教授 (40368626)
• 研究分担者: 柏原 直樹 川崎医科大学, 医学部, 教授 (10233701) ; 佐藤 稔 川崎医科大学, 医学部, 講師 (70449891)
• 研究期間 (年度): 2011 – 2013
• キーワード: アルブミン尿 / 内皮障害 / 一酸化窒素 / 慢性腎臓病

研究概要

慢性腎臓病CKDの中核病態であるアルブミン尿出現と心血管疾患発症の共通メカニズムを内皮機能障害に求め研究を行った。本研究の結果として、糖尿病では、1)糸球体内皮細胞障害がアルブミン尿出現に関与し、2)内皮機能障害の機序として、NO産生酵素（eNOS）の機能異常（eNOS uncoupling）が関与すること、3)酸化ストレスによるeNOS補酵素BH4の酸化・減少が関与することが判明した。また、酸化ストレス産生にはレニン・アンジオテンシン系（RA系）活性化とNADPH-oxidaseが関与しており、RA系抑制が内皮障害を抑制しアルブミン尿を減少させることが判明した。

研究成果

• [雑誌論文] Hypertension promotes islet morphological changes with vascular injury on pre-diabetic status in SHRsp rats (2014)
  • 著者名/発表者名: Satoh M, Nagasu H, Haruna Y, Ihoriya C, Kadoya H, Sasaki T, Kashihara N
  • 雑誌名: Clin Exp Hypertens 巻: 36(3) ページ: 159-64
  • DOI: 10.3109/10641963.2013.804539
  • 査読あり
• [雑誌論文] Angiotensin II Regulates Islet Microcirculation and Insulin Secretion in Mice (2013)
  • 著者名/発表者名: Ihoriya C, Satoh M, Kuwabara A, Sasaki T, Kashihara N
  • 雑誌名: Microcirculation
  • DOI: 10.1111/micc.12094
• [雑誌論文] Angiostatin production increases in response to decreased nitric oxide in aging rat kidney (2013)
  • 著者名/発表者名: Satoh M, Kidokoro K, Ozeki M, Nagasu H, Nishi Y, Ihoriya C, Fujimoto S, Sasaki T, Kashihara N
  • 雑誌名: Lab Invest 巻: 93(3) ページ: 334-43
  • DOI: 10.1038/labinvest.2012.171
  • 査読あり
• [雑誌論文] Maintenance of endothelial guanosine triphosphate cyclohydrolase I ameliorates diabetic nephropathy (2013)
  • 著者名/発表者名: Kidokoro K, Satoh M, Channon KM, Yada T, Sasaki T, Kashihara N
  • 雑誌名: J Am Soc Nephrol 巻: 24(7) ページ: 1139-50
  • DOI: 10.1681/ASN.2012080783
  • 査読あり
• [雑誌論文] Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status (2013)
  • 著者名/発表者名: Nishi Y, Satoh M, Nagasu H, Kadoya H, Ihoriya C, Kidokoro K, Sasaki T, Kashihara N
  • 雑誌名: Kidney Int 巻: 83(4) ページ: 662-73
  • DOI: 10.1038/ki.2012.475
  • 査読あり
• [雑誌論文] Chronic kidney disease, dyslipidemia, and atherosckerosis (2012)
  • 著者名/発表者名: Shoji T,Abe T,Kashihara N et al
  • 雑誌名: J Atheroscler Thromb 巻: 19(4) ページ: 299-315
  • DOI: 10.5551/jat.10454
  • 査読あり
• [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(3) ページ: 348-55
  • DOI: 10.1038/hr.2011.184
  • 査読あり
• [雑誌論文] Tacrolimus induces glomerular injury via endothelial dysfunction caused by reactive oxygen species and inflammatory change: idney (2012)
  • 著者名/発表者名: Kidokoro K, Satoh M, Nagasu H, Sakuta T, Kuwabara A, Yorimitsu D, Nishi Y, Tomita N, Sasaki T, Kashihara N
  • 雑誌名: Blood Press Res 巻: 35(6) ページ: 549-57
  • DOI: 10.1159/000339494
  • 査読あり
• [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(11) ページ: F1402-8
  • DOI: 10.1152/ajprenal.00459.2011
  • 査読あり
• [学会発表] Comparison of Combination Therapy with Irbesartan/Amlodipine and Irbesartan/Cilnidipine for Attenuation of Albuminuria in Rats with Streptozotocin-Induced Diabetic Nephropathy (2013)
  • 著者名/発表者名: Satoh M, Nishi Y, Kadoya H, Sasaki T, Kashihara N
  • 学会等名: ASN2013
  • 発表場所: Atlanta Georgia World Congress Center(Atlanta,USA)
  • 年月日: 2013-11-09
• [学会発表] Rosuvastatin Activates Transcription Factor Nrf2 through p21cip1 Expression and Prevents Albuminuria through Preservation of Glomerular Endothelial Integrity in AKITA Diabetic Mice (2013)
  • 著者名/発表者名: Ihoriya C, Satoh M, Sasaki T, Kashihara N
  • 学会等名: ASN2013
  • 発表場所: Atlanta Georgia World Congress Center(Atlanta,USA)
  • 年月日: 2013-11-09
• [学会発表] Implication of Inflammasome Activation via Mitochondrial Reactive Oxygen Species in the Development of Renal Interstitial Fibrosis Induced by Aldosterone (2013)
  • 著者名/発表者名: Kadoya H, Satoh M, Sasaki T, Kashihara N
  • 学会等名: ASN2013
  • 発表場所: Atlanta Georgia World Congress Center(Atlanta,USA)
  • 年月日: 2013-11-07
• [学会発表] T Type Ca-Channel Blocker Exerts Anti-Albuminuic Effect through Amelioration of eNOS Uncoupling in Hypertensive Kidney Disease Model (2013)
  • 著者名/発表者名: Itano S, Kidokoro K, Satoh M, Sasaki T, Kashihara N
  • 学会等名: ASN2013
  • 発表場所: Atlanta Georgia World Congress Center(Atlanta,USA)
  • 年月日: 2013-11-07
• [学会発表] Implications of Inflammasome-Activation in Macrophage on the Development of Renal Interstitial Inflammation and Fibrosis in Mice (2013)
  • 著者名/発表者名: Kadoya H, Satoh M, Itano S, Ihoriya C, Nishi Y, Kidokoro K, Komai N, Sasaki T, Kashihara N
  • 学会等名: ISN World Congress of Nephrology 2013
  • 発表場所: Hong Kong Convention and Exhibirion Centre(Hong Kong)
  • 年月日: 2013-06-02
• [学会発表] Rosuvastatin Maintain Glomerular Endothelial Surface layer Through Nrf2 Activation in Mouse Diabetic Nephropathy (2013)
  • 著者名/発表者名: Ihoriya C, Satoh M, Itano S, Kadoya H, Nishi Y, Kidokoro K, Komai N, Sasaki T, Kashihara N
  • 学会等名: ISN World Congress of Nephrology 2013
  • 発表場所: Hong Kong Convention and Exhibirion Centre(Hong Kong)
  • 年月日: 2013-06-01
• [学会発表] Klotho Protein Ameliorates Peritoneal Fibrosis Though The Regulation of Wnt/β-Catenin Signaling (2013)
  • 著者名/発表者名: Nishi Y, Satoh M, Itano Y, Sasaki T, Kashihara N
  • 学会等名: ISN World Congress of Nephrology 2013
  • 発表場所: Hong Kong Convention and Exhibirion Centre(Hong Kong)
  • 年月日: 2013-06-01
• [学会発表] Development of Novel Technique to Visualize in vivo Renin Activity and Analysis of Reno-Protective Actions of Renin Inhibitor in Diabetic Nephropathy (2013)
  • 著者名/発表者名: Kidokoro K, Satoh M, Nishi Y, Ihoriya C, Kadoya H, Komai N, Sasaki T, Kashihara N
  • 学会等名: ISN World Congress of Nephrology 2013
  • 発表場所: Hong Kong Convention and Exhibirion Centre(Hong Kong)
  • 年月日: 2013-06-01
• [学会発表] Endothelial dysfunction in pathogenesis of CKD (2013)
  • 著者名/発表者名: Satoh M
  • 学会等名: ISN World Congress of Nephrology 2013
  • 発表場所: Hong Kong Convention and Exhibirion Centre(Hong Kong)
  • 年月日: 2013-06-01
• [学会発表] Implication of inflammasome in the development of renal interstitial fibrosis induced by aldsoterone (2013)
  • 著者名/発表者名: Kadoya H, Satoh M, Sasaki T, Kashihara N
  • 学会等名: The 6th IAF Japan
  • 発表場所: Sendai
  • 年月日: 2013-04-28
• [学会発表] Implication of inflammasome in the development of renal interstitial fibrosis induced by aldsoterone (2013)
  • 著者名/発表者名: Kadoya H, Satoh M, Komai N, Sasaki T, Kashihara N
  • 学会等名: The 6^<th> International Aldosterone Forum in Japan
  • 発表場所: The Grand Hall(Tokyo)
  • 年月日: 2013-04-21
• [学会発表] Preservation of Endothelial GTP Cyclohydrolase I Activity and Improvement of Renal Nitric Oxide Availability Prevent the Development of Albuminuria in Diabetes (2012)
  • 著者名/発表者名: Kidokoro K, Satoh M, Yada T, Kashihara N
  • 学会等名: American Heart Association 2012
  • 発表場所: Los Angeles, USA
  • 年月日: 2012-11-07
• [学会発表] Spironolactone Suppresses the Inflammasome in Aldosterone Induced Renal Dysfunction via Blood Pressure Independent Pathway (2012)
  • 著者名/発表者名: Kadoya H, Satoh M, Sasaki T, Kashihara N
  • 学会等名: American Heart Association 2012
  • 発表場所: Los Angeles, USA
  • 年月日: 2012-11-06
• [学会発表] Erythropoietin Activates NAD(P)H Oxidase via Erythropoietin Receptor and Beta Common Receptor on Vascular Endothelial Cells (2012)
  • 著者名/発表者名: I horiya C,Satoh M, Kadoya H, Nishi Y, Sasaki T,Kashihara N
  • 学会等名: ASN2012
  • 発表場所: San Diego,USA
  • 年月日: 2012-11-03
• [学会発表] Rosuvastatin Activates Transcription Factor Nrf2 and Protects Prevents Albuminuria through Preservation of the Glomerular Endothelial Integrity in Akita Diabetic Mice (2012)
  • 著者名/発表者名: Ihoriya C,Satoh M, Sasaki T, Kashihara N
  • 学会等名: ASN2012
  • 発表場所: San Diego,USA
  • 年月日: 2012-11-03
• [学会発表] Stimulation of Soluble Guanylate Cyclase Attenuates Epithelial-Mesenchymal Transition of the Peritoneal Membrane and Prevent the Development of Peritoneal Fibrosis (2012)
  • 著者名/発表者名: Kadoya H, Satoh M, Nagasu H, Kidokoro K, Nishi Y, Ihoriya C, Sasaki T, Kashihara N
  • 学会等名: ASN2012
  • 発表場所: San Diego,USA
  • 年月日: 2012-11-02
• [学会発表] Klotho Attenuates Inflammation of Adipose Tissue and Development of Insulin Resistance in High-Fat Induced Obese Mice (2012)
  • 著者名/発表者名: Satoh M,Kidokoro K,Nagasu H,Ihoriya C,Nishi Y,Kadoya H,Sasaki T,Kashihara N
  • 学会等名: ASN2012
  • 発表場所: San Diego,USA
  • 年月日: 2012-11-02
• [学会発表] Overexpression of the Klotho Protein Attenuates Peritoneal Fibrosis by Suppressing Wnt-Signaling (2012)
  • 著者名/発表者名: Nishi Y,Satoh M, Sasaki T, Kashihara N
  • 学会等名: ASN2012
  • 発表場所: San Diego,USA
  • 年月日: 2012-11-02
• [学会発表] Development of a Novel Technique to Visualize In Vivo Renin Activity and Analysis of the Renoprotective Actions of a Renin Inhibitor (2012)
  • 著者名/発表者名: Kidokoro K, Satoh M, Sasaki T, Kashihara N
  • 学会等名: ASN2012
  • 発表場所: San Diego,USA
  • 年月日: 2012-11-01
• [学会発表] Nitric Oxide Attenuates Renal Fibrosis via Phosphorylation of Beta-Catenin (2012)
  • 著者名/発表者名: Nagasu H, Satoh M, Kadoya H, Sasaki T, Kashihara N
  • 学会等名: ASN2012
  • 発表場所: San Diego,USA
  • 年月日: 2012-11-01
• [学会発表] Klotho Protein Reduces Mouse Renal Fibrosis after Unilateral Ureteral Obstruction through Inhibition of Wnt Signaling (2012)
  • 著者名/発表者名: Satoh M, Nagasu H, Kidokoro K, Nishi Y, Ihoriya C, Kadoya H, Sasaki T, Kashihara N
  • 学会等名: 49th ERA-EDTA Congress
  • 発表場所: Le Palais des Congres de Paris(Paris,France)
  • 年月日: 2012-05-26
• [学会発表] Raloxifene Ameliorates Proteinuria-Induced Inflammasome Activation and Tubular Injury (2012)
  • 著者名/発表者名: Nishi Y,Satoh M, Sasaki T, Kashihara N
  • 学会等名: 49th ERA-EDTA Congress
  • 発表場所: Le Palais des Congres de Paris(Paris,France)
  • 年月日: 2012-05-26
• [学会発表] Endothelial Dysfunction promotes the Transition from Compensatory Renal Hypertrophy to Kidney Injury after Unilateral Neophrectomy in Mice (2012)
  • 著者名/発表者名: Kadoya H,Nagasu H,Satoh M,Sasaki T, Kashihara N
  • 学会等名: 49th ERA-EDTA Congress
  • 発表場所: Le Palais des Congres de Paris(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: Kidokoro 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: Le Palais des Congres de Paris(Paris,France)
  • 年月日: 2012-05-25
• [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: Le Palais des Congres de Paris(Paris,France)
  • 年月日: 2012-05-25