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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 investigate the synergistic protective effect of enalapril combined with mycophenolate mofetil (MMF) on diabetic nephropathy in rats and its mechanism. Methods STZ-induced diabetic rats model of unilateral nephrectomy were randomly divided into 5 groups: control group, model group, enalapril group, MMF group and enalapril combined with MMF group. After 8 weeks, the urinary albumin excretion rate (AER), renal pathology and malondialdehyde (MDA) content were compared with those of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase GSH-PX) activity changes. The expression of ED-1, ICAM-1 and TGF-β1 in renal tissue were detected by immunohistochemistry or Western blot. Results (1) Each administration group could inhibit the increase of AER and glomerular pathological damage in diabetic rats (P <0.05, 0.01). The combined administration group could significantly reduce the index of tubulointerstitial injury (P <0.05). (2) The improvement of MDA content and the decrease of SOD, CAT and GSH-PX activity in diabetic nephropathy group were better than that of single administration group (P <0.05, P <0.01). (3) ED-1 positive cells and ICAM-1 expression in glomeruli and tubulointerstitium in model group were significantly higher than those in control group (P <0.01); ED-1 positive cells in each group were significantly lower than those in model group (P <0.05, P <0.01). The expression of ICAM-1 in renal tissue in enalapril-treated group was not significantly different from that in model group, while the expression of ICAM-1 in MMF group and combined group was significantly lower than that in model group (P < 0.05). (4) Western blotting showed that the expression of TGF-β1 in diabetic renal tissue increased by 1.79-fold compared with the control group, and the expression of TGF-β1 in renal tissue in each administration group decreased by 39.72%, 44.80% and 55.09% respectively compared with the model group. Conclusion The combination of enalapril and MMF has a better protective effect on diabetic nephropathy than single drug treatment. The mechanism of enalapril and MMF is partly related to its synergistic inhibition on the increase of oxidative stress, inflammatory cell infiltration and TGFβ1 expression in renal tissue.