氟伐他汀对肾小球硬化大鼠Ⅳ型胶原的影响及分子机制研究

Effect of Fluvastatin on Collagen Type Ⅳ and Molecular Mechanism in Rats of Glomerular Sclerosis

目的:探讨羟甲基戊二酰辅酶A还原酶抑制剂氟伐他汀对肾小球硬化大鼠转化生长因子鄄β1(TGF鄄β1)的影响及其与纤维蛋白溶解酶原激活物抑制剂-1(PAI鄄1)、Ⅳ型胶原的关系。方法:用5/6肾切除的方法诱导大鼠肾小球硬化模型,随机分为对照组、氟伐他汀(2mg·kg-1·d-1),苯那普利(6mg·kg-1·d-1)及假手术组。10周时测尿量、尿蛋白、内生肌酐清除率(Ccr)、血肌酐、血胆固醇和血三酰甘油。肾组织行苏木精-伊红及PAS染色,并计算肾小球硬化指数(GSI),免疫组化检测肾组织Ⅳ型胶原水平表达,蛋白印迹测定肾皮质PAI鄄1、TGF鄄β1的蛋白水平表达。结果:氟伐他汀及苯那普利治疗组尿蛋白、GSI及肾组织Ⅳ型胶原表达明显低于对照组(P<0.01),PAI鄄1、TGF鄄β1表达亦低于对照组,Ccr明显高于对照组(P<0.01)。结论:氟伐他汀可抑制TGF鄄β1及PAI鄄1,减少Ⅳ型胶原积聚,减轻肾小球硬化,降低蛋白尿,改善肾功能,其对肾脏的保护作用并不依赖降胆固醇作用。

Objective: To investigate the effect of hydroxyl methylglulary coenzyme A reductase inhibitor(HCRI) fluvastatin on transforming growth factor-β1(TFG-β1), plasminogen activator inhibitolr-1(PAI-1) and collagen type Ⅳ in rats of glomerularsclerosis. Methods: Five sixths nephrectomized rats were randomly divided into 4 groups: control group, treated with fluvastatin group(2 mg·kg-1·d-1), treated with benazepril group(6 mg·kg-1·d-1)and pesudonephreotomized group. Urinary volume, proteinuria, creatinine clearance rate(Ccr), serum creatinine, cholesterol and triglyceride were reviewed after 10 weeks of treatment. Renal tisstues were stained by HE and PAS and glomerular sclerosis index(GSI) were caculated while the expression of TGF-β1, PAI-1 and collagen type Ⅳ protein were measured by the methods of Western Blotting and immunohistological staining respectively. Results: Proteinuria and the expressions of PAI-1, TGF-β1 collagen type Ⅳ, GSI in rats of fluvastatin and benazepril groups were significantly lower than the control(P < 0.01). Compared to control group, there was a significant increase in Ccr in groups treated with fluvastatin and benazepril(P < 0.01). Conclusion: Fluvastatin not only reduces proteinuria, improves renal function, but also modulates glomerular sclerosis by inhibiting activities of TGF-β1, PAI-1 and decreasing accumulation of collagen type Ⅳ. The mechanism of renal protective effect is independent of a reduction of circulating cholesterol.