氯沙坦对糖尿病大鼠肾脏结构、功能及肾组织p38MAPK的影响  

Effects of losartan on renal function and expression of phospho-p38 mitogen-activated protein kinase in early diabetic glomeruli

作　　者：王丽晖[1] 段惠军[1] 史永红[1] 刘青娟[1] 何宁[1] 刘淑霞[1] 高峰[1] 

机构地区：[1]河北医科大学病理教研室,河北石家庄050017

出　　处：《中国药理学通报》2004年第12期1393-1397,共5页Chinese Pharmacological Bulletin

基　　金：河北省自然科学基金资助项目;No3 0 2 5 00

摘　　要：目的　探讨特异性血管紧张素ⅡⅠ型受体拮抗剂氯沙坦对糖尿病大鼠肾脏结构、功能的保护机制及p38MAPK信号转导通路对此过程的作用。方法　♂Wister大鼠行右肾切除术 2wk后 ,随机分为 3组 ,右肾切除对照组、糖尿病组 ,氯沙坦治疗组。腹腔注射链脲佐菌素 (STZ ,6 5mg·kg-1)诱发糖尿病模型 ,氯沙坦 4 0mg·kg-1·d-1灌胃。分别于注射STZ后 4wk后各组选取 6只大鼠 ,收集尿液 ,测定尿蛋白(Upro) ,尿肌酐 (Ucr) ;股动脉放血分离血清 ,测定血糖(Glu)、血尿素氮 (BUN) ,血肌酐 (Scr)并计算肌酐清除率(Ccr)。免疫组化检测肾皮质磷酸化p38蛋白激酶 (p p38MAPK)及磷酸化cAMP反应元件结合蛋白 (p CREB)的表达特征 ,纤维粘连蛋白 (fibronectin ,FN )及层粘连蛋白(laminin ,LN)的表达 ,应用图像分析系统进行半定量分析。Westernblot及流式细胞术定量检测 p p38MAPK和 p CREB蛋白的表达。结果　与对照组相比 ,4wk时糖尿病模型组肾小球基底膜轻度增厚 ,细胞外基质 (ECM )增多 ,系膜区扩大 ,肾脏肥大指数升高 ,肾功能轻度受损 ,p p38MAPK、p CREB、FN及LN表达明显升高 ;而与糖尿病模型组相比 ,氯沙坦组肾脏结构 ,功能及各指标的表达有不同程度的降低。结论　氯沙坦对糖尿病大鼠肾脏结构和功能具有保护作用 。Aim To investigate the effects of Losartan on renal function and structure in experimental diabetic rats, to observe the function of p38 MAPK signal trusduction in this process. Methods Diabetes was induced in uninephrectomized male Wistar rats by intrapetitoneal injection of STZ(65 mg·kg -1) for 4 Weeks. Losartan(40 mg·kg -1) was administered daily by gavage from the next day of the induction for 4 weeks. Three groups were designed: Control(n=6),diabetic(n=6) and Losartan treatment(n=6) groups. Upro,Ucr in urine and Glu, Scr, BUN in serum were determined after 4wks. Immunohistochemistry combined with semi-quantitive method by computer image-pattern analysis system were used to analyze expression of p-p38 MAPK, p-CREB, FN and LN in renal glomeruli of different groups. Western blot and Flow cytometry were performed to valuate the expression of p-p38 MAPK and p-CREB in different groups. Results In diabetic rats, Losartan suppressed the expression of fibronectin and laminin in glomeruli, which was closely correlated to renal function,renal structure and renal hypertrophy index. In this study ,the activity and expression of p-p38 MAPK and p-CREB were observed in glomeruli in the diabetic group, which were inhibited by Losartan treatment. Conclusion Inhibition of glomerular p38 MAPK signal transduction pathyway may be responsible for the decrement of extracellular matrix accumulation and renal protective effects of losartan in uninephrectomized Wistar rats.

关 键 词：氯沙坦 糖尿病肾病 p38丝裂原活化蛋白激酶(p38 MAPK) 信号转导 磷酸化 

分 类 号：R-332[医药卫生] R322.61