波生坦和依那普利对糖尿病大鼠肾脏中过氧化物酶体增殖物激活剂受体γ途径的作用  

Effects of bosentan and enalapril on peroxisome proliferator-activated receptor-gamma pathway under diabetic conditions

作　　者：孙正达[1] 陈靖[1] 丁爽爽 邱长斌 杨海春[1] 朱蔚钰[1] 马骥[1] 顾勇[1] 林善锬[1] 

机构地区：[1]复旦大学附属华山医院肾内科,上海200040 [2]瑞士:Actelion Pharmaceuticals Ltd

出　　处：《中华肾脏病杂志》2003年第1期43-48,共6页Chinese Journal of Nephrology

基　　金：上海市教育委员会曙光计划(01SG08);99上海市教育委员会曙光计划项目;国家教育委员会霍英东基金;罗氏中国制药有限公司赞助基金

摘　　要：目的 探讨糖尿病状态下肾脏中过氧化物酶体增殖物激活剂受体(PPAR)γ途径的变化,以及此时应用内皮素受体拮抗剂bosentan和血管紧张素转化酶抑制剂enalapril对该途径的作用。方法采用单肾切除的小剂量链脲佐菌素(STZ)诱导的糖尿病大鼠模型,设非治疗组、bosentan治疗组、enalapril治疗组、两药合用组和单肾切除的对照组。分别采用免疫组织化学(组化)和RT-PCR等方法检测肾脏病变和PPARγ途径的情况,以及药物的作用。结果与糖尿病非治疗组相比,bosentan治疗组、enalapril治疗组和两药合用组的尿蛋白排泄量、肾小球细胞外基质(ECM)蛋白、肾脏转化生长因子(TGF)-β1和纤溶酶原激活物抑制物(PAI)-1的mRNA表达量均明显减少(P<0.01)。与正常对照组相比,4组模型动物肾脏PPARγ的mRNA表达量明显增加(P<0.01),而治疗组与非治疗组之间的PPARγ的mRNA表达量无明显变化。与正常对照组和非治疗组相比,肾脏的脂肪细胞-脂肪酸结合蛋白(A-FABP)的mRNA表达量在3个治疗组明显增加。与正常对照组相比,糖尿病非治疗组肾小球P-细胞外信号调节激酶(ERK)明显增加,而在3个治疗组则明显降低。结论 1型糖尿病大鼠肾脏内PPARγ的mRNA表达量明显增加,尽管bosentan和enalapril对此无明显作用,但两者都可以通过抑制ERK信号途径。Objective To investigate the changes of intrarenal peroxisome proliferator-activated receptor-'/(PPAR~/) pathway in diabetic rats and further evaluate the effects of angiotensin converting enzyme inhibitor(ACEI) enalapril and endothelin receptor antagonist (ERA) bosentan on this pathway. Methods Uninephrectomized male Wistar rats(180-200 g) were randomly assigned to five groups: low dose(35 mg/kg) streptozotocin-induced diabetic rats, bosentan-treated diabetic rats, enalapril-treated diabetic rats, bosentan + enalapril diabetic rats, and Uninephrectomized non-diabetic group. Immunohistochemistry and RT-PCR assay were used to detect the renal pathological changes and the PPARγ signaling pathway as well as the effects of bosentan and/or enalapril. Results Both bosentan and enalapril attenuated the urinary protein, the glomerular ECM deposition and the mRNA expression of TGF-β1 and PAI-1 in diabetic rats compared with those of untreated diabetic rats. The PPARγmRNA was up-regulated in the four diabetic groups and had no difference between the untreated group and the three treated groups. However, the mRNA expression of A-FABP, a specific target gene of PPARγ, which was unchanged in the untreated group, was significantly increased in the three treated groups. Results from immunohistochemistry indicated that p-ERK, which was remarkably increased in the untreated group, was decreased in the three treated groups. Conclusion Treatment with bosentan and/or enalapril significantly decreases the elevated p-ERK seen in the untreated diabetic group. The intrarenal PPARγ gene expression is up-regulated in the uninephrectomized STZ-induced diabetic rats. Although bosentan and enalapril have no effects on the intrarenal PPARγ mRNA, they can improve the transcription activity of PPARγ by inhibiting the ERK pathway, and this may ameliorate the progress of renal damage.

关 键 词：糖尿病 血管紧张素转化酶抑制剂 内皮素受体拮抗剂 过氧化物酶体增殖物激活剂受体γ 

分 类 号：R692.9[医药卫生—泌尿科学]