法舒地尔对盐敏感大鼠肾小球硬化症的弱化作用  

Fasudil attenuates glomerulosclerosis in Dahl salt-sensitive rats

作　　者：王新[1] 锦见俊雄 

机构地区：[1]首都医科大学附属北京安贞医院北京市心肺血管疾病研究所,北京100029 [2]日本独协医科大学病院循环内科

出　　处：《临床心血管病杂志》2011年第9期709-712,共4页Journal of Clinical Cardiology

摘　　要：目的:探讨Rho激酶通路是否参与高血压肾小球硬化症的发病机制,并评价Rho激酶抑制剂法舒地尔(Fasudil)的疗效。方法:Dahl盐敏感(DS)大鼠21只和盐抵抗(DR)大鼠12只从6周龄开始喂以高盐饮食形成肾衰竭模型。11周龄时将DS大鼠分为2组:DS-Fasudil组(9只)给予法舒地尔(mg.kg-1.d-1),DS组(12只)喂以0.9%氯化钠溶液,均7周。结果:7周后,与DR组大鼠相比,未治疗的DS组大鼠肾功能降低,蛋白尿增加,肾皮质的RhoB、Rho激酶α、Rho激酶β、胶原蛋白(Collagen)Ⅰ和CollagenⅢ、转化生长因子(TGF-β)的mRNA表达增加。与未治疗的DS组大鼠相比,DS-Fasudil组在没有改变血压水平的情况下明显改善肾功能(血清肌酐水平-26%,血尿素氮-41%,肌酐清降率+42%)。DS-Fasudil组明显降低了肾皮质TGF-β(-20%)、CollagenⅠ(-23%)、CollagenⅢ(-24%)mRNA的表达水平。但在DR组和DS-Fasudil组大鼠间上述参数没有明显的不同。结论:DS大鼠Rho激酶通路可能独立于血压之外,部分参与高血压肾小球硬化症的发病机制。Rho激酶通路抑制剂可能成为一种新的治疗高血压肾小球硬化症的手段。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：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-1·d-1） was administered for 7 weeks to DS starting at the age of 11 weeks. Result：After 7 weeks,untreated DS were characterized by decreased kidney function,increased proteinuria,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%） without changing blood pressure compared with untreated DS.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.

关 键 词：高血压 法舒地尔 肾小球硬化症 

分 类 号：R544.1[医药卫生—心血管疾病]