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Investigation on the role of Rho A in the progression of renal injury

Research Project

Project/Area Number 12671048
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionKeio University

Principal Investigator

HAYASHI Koichi  Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (80164937)

Co-Investigator(Kenkyū-buntansha) OKUBO Ken  Keio University, School of Medicine, Assistant, 医学部, 助手 (30286455)
徳山 博文  慶應義塾大学, 医学部, 助手 (50276250)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2000: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsRho kinase / afferent arterioles / efferent arterioles / hypertension / proteinuria / chronic renal failure / RhoA / 腎微小循環
Research Abstract

A growing number of studies have demonstrated that Rho kinase participates importantly in the vasomotor regulation, as well as in the pathogenesis of various diseases, including vascular hypertrophy and atherosclerosis. The aims of the current project are to clarify the role of Rho kinase in mediating the control of renal vascular tone under basal and angiotensin II-stimulated conditions in renal arterioles of Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), using the isolated perfused hydronephrotic rat kidney. When administered under basal vascular tone, Y-27632 caused dose-dependent dilation of afferent arterioles in WKY and SHR. Y-27632 also reversed angiotensin II-induced afferent arteriolar vasoconstriction, with 83% reversal at 10^<-5> mol/l in WKY. In contrast, the ability of Y-27632 to inhibit the KCl-induced afferent arteriolar constriction was diminished; only 38% reversal was observed at 1-^<-5> mol/l. In SHR, Y-27632 inhibited the angiotensin II-induced a … More fferent arteriolar constriction to the degree similar to that observed in WKY. The Y-27632-induced vasodilation of KCl-constricted afferent arterioles, however, was enhanced in SHR, compared with that in WKY. We further examined the effect of fasudil, a Rho-kinase inhibitor, on the progression of renal injury in salt-loaded subtotally nephrectomized SHR (SHR-Nx). In SHR-Nx treated with fasudil (3 mg/kg/day, ip), systolic blood pressure was progressively elevated (from 151±4 to 208±8 mmHg at 8 weeks, n=8), which was not different from that in SHR-Nx without fasudil (from 149±3 to 217±14mmHg, n=8). Urinary protein excretion was markedly increased in SHR-Nx (from 21±1 to 124±16mg/day at 8 weeks), but this increase was significantly suppressed by fasudil (to 79±12mg/day at 8 weeks). Renal histological examination revealed that fasudil improved glomerular (77±5 vs. 60±5, p<0.05) and tubulointerstitial injury scores )1.7±0.3 vs. 0.8±0.2, p<0.05), with parallel amelioration of proliferating cell nuclear antigen-positive cell infiltration (glomerulus, 30±4 vs. 18±3, p<0.05; tubulointerstitium, 12±1 vs. 5±2, p<0.05). In conclusions, the present study demonstrates important roles of Rho kinase pathways in mediating the renal arteriolar tone. The contribution of Rho kinase- associated calcium sensitivity to the renal arteriolar constriction, however, differs, depending on the underlying vasoconstrictor stimuli used. Furthermore, the role of Rho/ROCK in renal vasoconstriction was altered in SHR. Finally, Rho-kinase pathway is involved in the pathogenesis of renal injury, and we suggest that the inhibition of Rho-kinase may constitute a therapeutic strategy for the treatment of renal injury. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (9 results)

All Other

All Publications (9 results)

  • [Publications] Nagahama T: "Role of protein kinase C in angiotensin II-induced constriction of renal microvasculature"Kidney International. 57. 215-223 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 中村 玲: "腎輸入・輸出細動脈抵抗調節におけるRho/ROCK系の役割"慶應医学. 78. 21-30 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Honda M: "Divergent renal vasodilator action of L-and T-type calcium antagonists in vivo"Journal of Hypertension. 19. 2031-2037 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nagahama T, et al.: "Role of protein kinase C in angiotensin II-induced constriction of renal microvasculature"Kidney International. 57. 215-223 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakamura A.: "Role of Rho/ROCK in afferent arteriolar tone"Keio Igaku. 78. 21-30 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Honda M, et al.: "Divergent renal vasodilator action of L- and T-type calcium antagonists in vivo"Journal of Hypertension. 19. 2031-2037 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Honda M: "Divergent renal vasodilator action of L-and T-type calcium antagonists in vivo"Journal of Hypertension. 19(11). 2031-2037 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nagahama T: "Role of protein kinase C in angiotensin II-induced constriction of renal microvasculature"Kidney International. 57. 215-223 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 中村玲: "腎輸入・輸出細動脈抵抗調節におけるRho/ROCK系の役割"慶應医学. 78(1). 21-30 (2001)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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