Investigation on the mechanisms of association of chronic kidney disease(CKD) and cardiovascular diseases.

• Project/Area Number: 21591047
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kawasaki Medical School
• Principal Investigator: KASHIHARA Naoki 川崎医科大学, 医学部, 教授 (10233701)
• Co-Investigator(Kenkyū-buntansha): TOMITA Naruya 川崎医科大学, 医学部, 准教授 (70314432) ; SATOH Minoru 川崎医科大学, 医学部, 講師 (70449891)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 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

Research Abstract

Albuminuria is strongly associated with cardiovascular diseases. Endothelial dysfunction has been speculated to be involved in the pathogenesis of albuminuria. We have successfully developed a novel in vivo imaging technique which enables us to visualize microcirculation and permeability change in the kidney. Using this technique, we found hyperfiltration of macromolecules precede albuminuria. We also demonstrated endothelial dysfunction, indicated by the loss of glycocalyx along the glomerular vascular wall and uncoupling of eNOS is deeply involved in this condition.

Research Products

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