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

基本信息

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

项目摘要

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激酶重要地参与了血管舒缩调节，以及各种疾病（包括血管肥大和动脉粥样硬化）的发病机理。当前项目的目的是阐明Rho激酶在Wistar Kyoto大鼠（WKY）的肾动脉中介导肾血管张力和血管紧张素II刺激的条件下的作用，并使用孤立的灌注性灌注的水生细胞性抑制性养育性大鼠（SHR）（SHR）的肾动脉中的作用。 Y-27632在基本血管张力下给药时，在WKY和SHR中引起了传入小动脉的剂量依赖性词典。 Y-27632还逆转了血管紧张素II诱导的传入小动脉血管收缩，在WKY中为10^<-5> mol/l的83％反转。相反，Y-27632抑制KCl诱导的传入小动脉收缩的能力降低了。在1-^<-5> mol/L处仅观察到38％的逆转。在SHR中，Y-27632抑制了血管紧张素II诱导的A…更加轻率的小动脉收缩，其程度与WKY中观察到的程度相似。与WKY相比，SHR的Y-27632诱导的KCl构成的传入小动脉的血管舒张增强了。我们进一步研究了一种Rho-激酶抑制剂Fasudil对盐载盐肾上腺切除型SHR（SHR-NX）中肾脏损伤的进展。在用fatigueil（3 mg/kg/day，ip）处理的SHR-NX中，收缩压逐渐升高（在8周时从151±4到208±8 mmHg，n = 8），这与没有FATIGUEIL的SHR-NX没有什么不同（从没有Fatigueil（从149±3到149±3至3至317±3至217±14mmMHg，n = 8）。 SHR-NX中的尿蛋白极端显着增加（8周在8周时从21±1到124±16mg/天），但是Fasudil显着抑制了这种增加（在8周时为79±12mg/天）。肾脏组织学检查表明，法曲尔改善了肾小球（77±5 vs. 60±5，p <0.05）和tubelointerstitial损伤评分）1.7±0.3 vs. 0.8±0.2，p <0.05），并平行地放整个增殖细胞核抗原抗原细胞插入率（30 30 cl）（glopol杂种）（glopol杂种）（glopol杂种）（ p <0.05;总而言之，本研究表明，Rho激酶途径在介导肾动脉张力中的重要作用。然而，Rho激酶相关的钙敏感性对肾动脉收缩的敏感性取决于所使用的基本血管收缩刺激。此外，Rho/Rock在肾血管收缩中的作用在SHR中发生了改变。最后，Rho-kinase途径参与肾损伤的发病机理，我们建议抑制Rho-激酶可能构成治疗肾损伤的治疗策略。