洛伐他汀对糖尿病大鼠肾功能及肾脏组织p38丝裂原激活蛋白激酶表达的影响

目的 探讨洛伐他汀对糖尿病(DM)大鼠肾小球结构、功能及肾组织p38丝裂原活化蛋白激酶(MAPK)及其下游转录因子cAMP反应元件结合蛋白(cREB)表达的影响。方法 18只雄性Wistar大鼠行右肾切除术2周后,随机分为3组:右肾切除对照组、DM组和洛伐他汀治疗组每组6只。DM组和洛伐他汀组腹腔注射链脲佐菌素(STZ,65 mg／kg)诱发DM模型,洛伐他汀组制模后1 d每日给予洛伐他汀20 mg／kg灌胃。分别于注射STZ后4周收集大鼠尿液,测定尿蛋白(Upro)、尿肌酐(UCr);股动脉放血分离血清,测定血糖(Glu)、血肌酐(SCr)、尿素氮(BUN)、胆固醇(CHO)和甘油三酯(TG),并计算肌酐清除率(CCr)。免疫组化检测肾皮质磷酸化p38 MAPK(P-p38 MAPK)及磷酸化CREB(P-CREB)的表达特征,并检测转化生长因子-β1(TGF-β1)、纤维粘连蛋白(FN)及层粘连蛋白(LN)的表达,应用图像分析系统进行定量分析。流式细胞术检测P-p38 MAPK和P-CREB蛋白的表达,Western印迹法检测肾皮质P-p38 MAPK和P-CREB活性的变化。结果 与对照组相比,4周时DM组P-p38 MAPK、P-CREB、TGF-β1、FN及LN表达均明显升高(P均<0.01);而与DM组相比,洛伐他汀组各指标的表达有不同程度的降低(P均<0.01)。结论 洛伐他汀对DM大鼠肾脏结构和功能具有保护作用,可能通过调节p38 MAPK和CREB蛋白的表达

Effects of lovastatin on renal function and expression of phosphorylating-p38 mitogen-activated protein kinase in experimental diabetic nephropathy in rats

OBJECTIVE: To investigate the effects of lovastatin on renal function, activity and expression of the p38 mitogen-activated protein kinase (MAPK) and cAMP responsive element-binding protein (CREB) in experimental diabetic nephropathy in rats. METHODS: Eighteen uninephrectomized male Wistar rats were randomly divided into three groups: control (n=6), diabetic (n=6) and lovastatin treatment group (n=6). Diabetes was induced by intraperitoneal injection of STZ (65 mg/kg). Lovastatin (20 mg/kg) was administered daily by gavage from the next day of the induction diabetes for 4 weeks. Four weeks later, animals were sacrificed and samples were collected to determine various parameters, including protein and creatinine in urine (Upro and UCr), and glucose (Glu), creatinine (SCr), blood urea nitrogen (BUN) in serum. Immunohistochemistry and computer image-pattern analysis system were used to analyze activation of P-p38 MAPK and P-CREB, the expression of transferase growth factor-beta(1) (TGF-beta(1)), fibronectin (FN), laminin (LN) in renal glomeruli were also measured. RESULTS: Expression of P-p38 MAPK and P-CREB in diabetic glomeruli in diabetic rats were higher than the controls, the same as the expression of TNF-beta(1), FN, LN(all P<0.01). After lovastatin treatment, expression of P-p38 MAPK, P-CREB and TGF-beta(1), FN, LN were markedly decreased compared with diabetic group(all P<0.01). CONCLUSION: Inhibition of glomerular p38 MAPK signal transduction pathway may be responsible for the decrement of extracellular matrix accumulation and renal protective effects of lovastatin in uninephrectomized rats.