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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: To investigate whether Rho kinase pathway is involved in the pathogenesis of hypertensive glomerulosclerosis and to evaluate the efficacy of Rho kinase inhibitor Fasudil. METHODS: Twenty-one Dahl salt-sensitive (DS) rats and 12 rats of salt-resistant (DR) rats were fed a high-salt diet from 6 weeks to develop a model of renal failure. At 11 weeks of age, DS rats were divided into two groups: fasudil (mg.kg-1.d-1), DS-Fasudil (n = 9) Sodium solution, all 7 weeks. RESULTS: After 7 weeks, the renal function and proteinuria of untreated DS rats were decreased compared with those in DR group. RhoB, Rho kinase, Rho kinase, Collagen I and Collagen III in renal cortex , Transforming growth factor (TGF-β) mRNA expression increased. The DS-Fasudil group improved renal function (serum creatinine level -26%, blood urea nitrogen -41%, creatinine clearance rate + 42%) without alteration of blood pressure compared with untreated DS group . The expression of TGF-β (-20%), CollagenⅠ (-23%) and CollagenⅢ (-24%) mRNA in renal cortex were significantly decreased in DS-Fasudil group. However, there was no significant difference in the above parameters between the DR group and the DS-Fasudil group. Conclusion: Rho kinase pathway in DS rats may be independent of blood pressure, and partly participate in the pathogenesis of hypertensive glomerulosclerosis. Rho kinase pathway inhibitors may become a new means of treating hypertensive glomerulosclerosis.