Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats
Fasudil, a Rho-kinase inhibitor, attenuates glomerulosclerosis in Dahl salt-sensitive rats
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DOI：
10.1097/00004872-200409000-00024
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发表时间：
2004-09-01
影响因子：
4.9
通讯作者：
Matsuoka, H
中科院分区：
文献类型：
--
作者：
Nishikimi, T;Akimoto, K;Matsuoka, H
目的探讨Rho激酶通路是否参与了高血压肾小球硬化的形成过程，并观察Rho激酶特异性抑制剂法舒地尔（fasudil）对高血压肾小球硬化的治疗作用。从11周龄开始，法舒地尔（30 mg/kg/天）给药7周至DS。7周后，未治疗的DS的特征为肾功能下降、蛋白尿增加、异常形态学发现、肾上腺髓质素和心钠素（ANP）水平升高以及RhoB、Rho-激酶α、Rho-激酶β、胶原I和胶原III的肾脏信使RNA表达增加，和转化生长因子-β与DR相比，慢性法舒地尔治疗显著改善了肾功能（血清肌酐，-26%;血尿素氮，-41%;肌酐清除率，+42%）、蛋白尿（-24%）和组织学结果（肾小球损伤评分，-49%;传入小动脉损伤评分，-17%），与未治疗的DS相比，没有改变血压。有趣的是，长期法舒地尔治疗降低了血浆肾上腺髓质素（-25%）和ANP（-49%），但没有改变血浆肾素或醛固酮。此外，法舒地尔显著降低肾皮质中TGF-β（-20%）、胶原I（-23%）和胶原III（-24%）的信使RNA表达。结论Rho-Rho-kinase通路可能是DS高血压性肾小球硬化的发病机制之一，而与血压无关，长期抑制Rho-Rho-kinase通路可能是治疗高血压性肾硬化的新策略。(C)2004年利平科特威廉姆斯威尔金斯。
Objective The present study was designed to clarify whether the Rho-Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil, a specific Rho-kinase inhibitor.Method and results Dahl salt-sensitive rats (DS) and Dahl salt-resistant rats (DR) were fed a high-salt diet at 6 weeks of age. Fasudil (30 mg/kg per day) was administered for 7 weeks to DS starting at the age of 11 weeks. After 7 weeks, untreated DS were characterized by decreased kidney function, increased proteinuria, abnormal morphological findings, increased adrenomedullin and atrial natriuretic peptide (ANP) levels, and increased renal messenger RNA expression of RhoB, Rho-kinasealpha, Rho-kinasebeta, collagen I and collagen III, and transforming growth factor-beta (TGF-beta) in the renal cortex compared with DR. Chronic fasudil treatment significantly improved renal function (serum creatinine, -26%; blood urea nitrogen, -41%; creatinine clearance, +42%), proteinuria (-24%) and histological findings (glomerular injury score, -49%; afferent arteriolar injury score, -17%) without changing blood pressure compared with untreated DS. Interestingly, long-term fasudil treatment decreased the plasma adrenomedullin (-25%) and ANP (-49%), but did not change the plasma renin or aldosterone. Furthermore, fasudil significantly decreased the messenger RNA expression of TGF-beta (-20%), collagen I (-23%), and collagen III (-24%) in the renal cortex. However, there were still significant differences in the aforementioned parameters between DR and fasudil-treated DS.Conclusion These results suggest that the Rho-Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis independently of blood pressure in DS, and that chronic inhibition of the Rho-Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis. (C) 2004 Lippincott Williams Wilkins.