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

Rho A在肾损伤进展中的作用研究

• 批准号: 12671048
• 负责人: HAYASHI Koichi
• 金额: $ 2.05万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671048/
• 关键词: Rho kinase; afferent arterioles; efferent arterioles; hypertension; proteinuria; chronic renal failure; RhoA; 腎微小循環

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

越来越多的研究表明，Rho激酶参与了血管活性的调节，并参与了多种疾病的发病机制，包括血管肥大和动脉粥样硬化。本项目的目的是阐明Rho激酶在调节基础和血管紧张素II刺激条件下Wistar京都大鼠（WKY）和自发性高血压大鼠（SHR）肾小动脉中肾血管张力控制中的作用。当在基础血管张力下给药时，Y-27632引起WKY和SHR中传入小动脉的剂量依赖性扩张。Y-27632还逆转血管紧张素II诱导的传入小动脉血管收缩，在WKY中10 μ mol/l时逆转率为83%<-5>。相比之下，Y-27632抑制KCl诱导的传入小动脉收缩的能力减弱;在1 μ mol/l时仅观察到38%的逆转<-5>。在SHR中，Y-27632抑制血管紧张素II诱导的血管紧张素II受体的表达。 ...更多信息 传入小动脉收缩程度与WKY相似。然而，与WKY相比，Y-27632诱导的KCl收缩的传入小动脉的血管舒张在SHR中增强。我们进一步研究了Rho激酶抑制剂法舒地尔对盐负荷肾大部切除SHR（SHR-Nx）肾损伤进展的影响。法舒地尔组（3 mg/kg/d，ip）收缩压进行性升高（8周时从151±4升至208±8 mmHg），与未用法舒地尔组（149±3升至217± 14 mmHg）无明显差异。SHR-Nx组尿蛋白排泄量明显增加（8周时从21±1增加到124± 16 mg/d），但法舒地尔组尿蛋白排泄量明显减少（8周时为79± 12 mg/d）。肾组织学检查显示，法舒地尔改善肾小球肾小管间质损伤评分（77±5 vs.60 ±5，p&lt;0.05）和肾小管间质损伤评分（1.7±0.3 vs.0.8 ±0.2，p&lt;0.05），同时伴有增殖细胞核抗原阳性细胞浸润的平行改善（肾小球，30±4对18±3，p&lt;0.05;肾小管，12±1对5±2，p&lt;0.05）。总之，本研究表明Rho激酶通路在介导肾小动脉张力中的重要作用。然而，Rho激酶相关的钙敏感性对肾小动脉收缩的贡献不同，这取决于所使用的潜在血管收缩刺激。此外，Rho/ROCK在SHR肾血管收缩中的作用发生了改变。最后，Rho激酶通路参与了肾损伤的发病机制，我们认为抑制Rho激酶可能成为肾损伤的治疗策略。少

项目成果

Nakamura A.: "Role of Rho/ROCK in afferent arteriolar tone"Keio Igaku. 78. 21-30 (2001)

Nakamura A.：“Rho/ROCK 在传入小动脉音调中的作用”Keio Igaku。

Honda M: "Divergent renal vasodilator action of L-and T-type calcium antagonists in vivo"Journal of Hypertension. 19. 2031-2037 (2001)

Honda M：“L-和T-型钙拮抗剂在体内的不同肾血管舒张作用”高血压杂志。

Honda M, et al.: "Divergent renal vasodilator action of L- and T-type calcium antagonists in vivo"Journal of Hypertension. 19. 2031-2037 (2001)

Honda M 等人：“体内 L 型和 T 型钙拮抗剂的不同肾血管舒张作用”高血压杂志。

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

Nagahama T：“蛋白激酶 C 在血管紧张素 II 诱导的肾微血管收缩中的作用”肾脏国际。

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)

Rei Nakamura：“Rho/ROCK 系统在调节肾脏输入和传出小动脉阻力中的作用”Keio Medical Science 78. 21-30 (2001)。