氟伐他汀对糖尿病大鼠肾小管间质病变的保护作用及其机制

Effects of fluvastatin on the tubulointerstitium in progressive diabetic kidney disease

目的 观察氟伐他汀对实验性 2型糖尿病大鼠肾小管间质病变的保护作用。 方法 应用单侧肾切除加饮食加小剂量链脲佐菌素 (30mg/kg)方法 ,制备 2型糖尿病肾病大鼠模型。将实验动物随机分为对照组、糖尿病组及治疗组。治疗组给予氟伐他汀 (2mg/kg)治疗 6周后 ,检测各组大鼠血糖、胰岛素、血脂、血肌酐、2 4h尿蛋白定量等指标。采用免疫组织化学技术检测各组肾小管间质中c Jun、转化生长因子 (TGF) β1 蛋白表达水平。采用RT PCR方法检测TGF β1 mRNA表达水平。 结果 治疗 6周后 ,小剂量氟伐他汀对血糖、血脂水平无影响 ,但可明显降低 2型糖尿病肾病大鼠肾小管间质中c Jun(0 2 5 36± 0 0 1 80对 0 5 85 5± 0 0 31 4 ,P <0 0 1 )、TGF β1 蛋白 (0 1 835±0 0 0 4 7对 0 3973± 0 0 0 5 2 ,P <0 0 1 )及TGF β1 mRNA (0 2 5 5 3± 0 0 0 2 1 5对 0 8932± 0 0 36 3,P <0 0 1 )的表达 ,并减少蛋白尿 (0 1 835± 0 0 0 4 7对 2 6 5 3± 7 33,P <0 0 5 )。 结论 氟伐他汀对糖尿病肾小管间质病变具有非依赖降脂的保护作用 ,其机制至少部分与下调肾小管间质中活化蛋白(AP) 1 (c Fos /c Jun)和TGF β1

Objective To investigate the effects of fluvastatin on the tubulointerstitium damage in progressive diabetic kidney disease. Methods A rat model of type 2 diabetic nephropathy (DN) was developed successfully by combination of dietary induced insulin resistance and low dose STZ induced hyperglycemia after unilateral nephrectomy. Female SD rats were randomly divided into three groups: control rats, type 2 diabetic rats and type 2 diabetic rats treated with fluvastatin (2mg/kg/d). After 6 weeks, blood glucose, serum insulin, serum triglyceride and cholesterol, serum creatinine, and urinary protein were measured respectively. The protein expressions of c Jun and tansforming growth factor (TGF) β 1 were studied by immunohistochemistry. TGF β 1 gene expression was studied with a RT PCR technique. Results Fluvastatin at lower doses, which did not influence blood glucose and blood lipid level, significantly inhibited expression of c Jun protein(0 2536±0 0180 vs 0 5855±0 0314, P <0 01), down regulated expression of TGF β protein(0 1835±0 0047 vs. 0 3973±0 0052, P <0 01)and its mRNA(0 2553±0 00215 vs. 0 8932±0 0363, P <0 01) and lowered urine protein excretion (0 1835±0 0047 vs. 26 53±7 33, P <0 05) after 6 weeks. Conclusions Fluvastatin can prevent tubulointerstitium damage in progressive diabetic kidney disease independent of cholesterol lowering effects. The mechanism may be associated, at least in part, with down regulating the AP 1(c fos / c Jun)and TGF β 1 expression in tubulointerstitium in type 2 DN.