依那普利联合霉酚酸酯对大鼠糖尿病肾脏协同保护作用及机制

Superior renoprotective effects of the combination of enalapril with mycophenolate mofetil and its mechanism in diabetic rats

目的探讨依那普利联合霉酚酸酯(MMF)对大鼠糖尿病肾脏协同保护作用及其机制。方法建立STZ诱导的大鼠单侧肾切除糖尿病模型,随机分5组:对照组、模型组、依那普利组、MMF组及依那普利与MMF联合给药组。8周后观察尿白蛋白排泄率(AER)、肾组织病理及丙二醛MDA)含量与超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱苷肽过氧化物酶(GSH-PX)活性变化。免疫组化或Western印迹检测肾组织ED-1、ICAM-1与TGF-β1蛋白表达。结果(1)各给药组均可抑制糖尿病大鼠AER增加及肾小球病理损害(P<0.05,0.01);联合给药组可明显减轻糖尿病肾小管间质损伤指数(P<0.05)。(2)对糖尿病肾组织MDA含量增加及SOD、CAT与GSH-PX活性降低的改善作用,联合组优于单给药组(P<0.05,P<0.01)。(3)模型组肾小球与肾小管间质ED-1阳性细胞数与ICAM-1表达明显高于对照组(P<0.01);各给药组ED-1阳性细胞数明显低于模型组(P<0.05,P<0.01);依那普利给药组肾组织ICAM-1表达与模型组相比差异无统计学意义,MMF与联合组ICAM-1表达明显低于模型组(P<0.05)。(4)Western印迹显示糖尿病肾组织TGF-β1表达较对照组增加1.79倍,各给药组肾组织TGF-β1表达较模型组分别下降39.72%,44.80%与55.09%。结论依那普利与MMF联合给药对糖尿病肾脏保护作用优于单种药物治疗,其机制部分与其对肾组织氧化应激增加、炎症细胞浸润及TGFβ1表达有协同抑制作用有关。

Objective To assess superior reaoproteetive effects of the combination of enalapril with mycophenolate mofetil （MMF） and its mechanism in diabetic rats. Methods Diabetes was induced by injection of streptozotocin after uninephrectomy. Rats were randomly separated into five groups： control, diabetes, diabetes treated with enalapril, diabetes treated with MMF, and diabetes treated with combined enalapril and MMF. Albumin excretion rate （AER）, the level of malondialdehyde （MDA） and activities of antioxidant in renal tissue were determined, and renal tissue morphology was observed by light microscopy after 8 weeks. Expression of ED-1, ICAM-1 and TGF-β1 protein was examined by immunohistochemistry or Western blot. Results Diabetes was associated with a considerable increase in albumin excretion rate. Both enalapril and MMF retarded the increase in albuminuria, which was nearly completely abrogated by combination therapy. Glomerular volume in diabetic rats was attenuated by treatment with either enalapril or MMF and further reduced by the combination of the two. Increased tubulointerstitial injury index was not lowered by enalapril or MMF treatment but reduced by the combination therapy in both cases. Elevated malondialdehyde level and decreasedactivities of superoxide diamutase, catalase and glutathione peroxidase in renal tissue were remitted by enalapril or MMF and, more effectively, by combined enalapril with MMF. Renal overexpression of ICAM-1 was not retarded by enalapril but attenuated by MMF or combined enalapril with MMF. Combination therapy was asseeiated with a superior suppression in diabetes-induced maerophage recruitment and overexpression of TGF-β1 compared to either monotherapy in renal tissue. Conclusion The combination of enalapril and MMF confers superiority over monotherapies on renoproteetion, whose mechanism may be at least partly related with synergetic suppression on increased oxidative stress and maerophage recruitment as well as overexpression of TGF-β1 in renal tissue.