氟伐他汀对环孢素A致大鼠肾毒性的保护作用

Effects of fluvastatin on renal fibrosis induced by cyclosporine A

摘要:

目的：观察羟甲基戊二酰辅酶A还原酶抑制剂氟伐他汀（fluvastatin，Flu）对环孢素A（cyclosporine A，CsA）致大鼠肾毒性的保护作用。方法：选择30只健康、雄性SD大鼠，随机分为3组：①对照组：给予蒸馏水和橄榄油灌胃；②肾毒性组：给予CsA 30 mg/（kg·d）；③治疗组：给予CsA 30 mg/（kg·d）和Flu 7 mg/（kg·d）。在灌药后的第14天，每组随机处死5只大鼠，实验的第28天，处死其余的大鼠，观察各组肾脏组织学变化，用免疫组织化学技术检测肾组织中Smad2/3、Smad7蛋白及转化生长因子-β1（transforming growth factor-β1，TGF-β1）的表达情况。各组大鼠在每周抽血检测肾功能和脂类水平。结果：在第1周，Flu治疗组的血肌酐（serum creatinine，SCr）与对照组差异无统计学意义（P=0.564）。肾毒性组从第1周开始SCr增高（P=0.000）。肾毒性组在第14天和第28天肾脏的纤维化评分、Smad2/3蛋白及TGF-β1的表达与对照组比较增加（P=0.000），而Smad7蛋白表达明显下调（P=0.000），Flu在这2个时间点能够不同程度地改善这些指标。3组的胆固醇水平在第0、1、2、3和4周之间的差异无统计学意义（P=0.865、0.997、0.505、0.871及0.540），同时各组的甘油三酯水平在相同时间点比较差异无统计学意义（P=0.894、0.663、0.826、0.635及0.928）。治疗组与肾毒性组在第2周和第4周CsA的谷值浓度比较均无统计学差异（P=0.183和P=0.123）。结论：Flu对环孢素A致大鼠肾毒性有保护作用。

Abstract:

Objective：To observe the effects of hydroxymethylglutaryl coenzyme A reductase inhibitor fluvastatin（Flu） on renal fibrosis induced by cyclosporine A（CsA） in rats． Methods：Totally 30 adult male SD rats were randomly divided into three groups．Controls were fed with olive oil，CsA treated rats were given CsA（30 mg/（kg·d）），and Flu treated rats were given CsA（30 mg/（kg·d）） and Flu（7 mg/（kg·d）） by gavage． Five rats of each group were sacrificed on the 14th d and the others were sacrificed at the end of the study（the 28th d）. Histological changes in renal tissue were observed． Sites and levels of expression of Smad protein 2/3，Smad protein 7 and transforming growth factor-β1（TGF-β1） were examined by immunohislochemistry staining． Renal function and lipid levels were measured in every week． Results：Serum creatinine（SCr） in Flu treated group on the 7th d was all equivalent to that of control group（P=0.564）． From the first week after treatment，levels of SCr in CsA treated group were significantly increased compared with those in control group（P＝0.000）． Compared with those of control group，Smad protein 2/3 and TGF-β1 expression on the 14th and 28th d was significantly increased in CsA treated rats（P＝0.000），while Smad protein 7 expression was markedly decreased（P＝0.000）． These lesions were significantly ameliorated by Flu. Levels of total cholesterol（P=0.865，0.997，0.505，0.871，0.540），triglyc－erides（P=0.894，0.663，0.826，0.635，0.928） had no statistical difference at same time point among all three groups. CsA valley con－centration had no statistical difference between Flu treated group and CsA treated group（P=0.183，P=0.123）． Conclusion：Flu could slow the progression of cyclosporine nephropathy.