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目的:研究缬沙坦联合苯那普利对糖尿病大鼠足细胞损伤的影响及肾脏保护机制的作用。方法:将SD大鼠随机分为正常对照组(A组),糖尿病对照组(B组),糖尿病苯那普利治疗组(C组),糖尿病缬沙坦治疗组(D组),缬沙坦联合苯那普利(E组)。分别于实验第4、6周末各组随机取8只测定大鼠平均动脉压、血糖、血肌酐、尿肌酐、肾重/体重、尿白蛋白排泄率,对肾脏标本进行光镜、电镜观察,用图像分析仪测量各组大鼠的平均肾小球横截面积、平均肾小球体积,并于6周末用逆转录-PCR(RT-PCR)方法检测各组肾皮质TGF-β1 mRNA表达。采用免疫组织化学染色检查足细胞特异标记物nephrin、desmin,对足细胞进行准确的定位及其密度定量观察,同时结合临床和肾组织病理有关指标进行分析。结果:苯那普利、缬沙坦、缬沙坦联合苯那普利治疗均使Ccr、肾重/体重、尿白蛋白排泄率、TGF-β1 mRNA表达降低,而缬沙坦联合苯那普利组对TGF-β1 mRNA抑制程度最大,同时肾脏病理变化亦最轻。B组、E组均伴肾小球足细胞数目及密度的减少,其中以B组最为显著,C组、D组次之,E最轻。足细胞数目及其密度与尿蛋白量呈显著负相关(P<0.01)。nephrin、desmin在A组沿肾小球基底膜呈连续、线形分布。C组、D组、E组nephrin、desmin的表达量降低,与正常组织比较,无统计学意义,B组nephrin、desmin的表达呈点状、短线条状,与正常组织比较,有统计学意义(P<0.05)。糖尿病大鼠足细胞数目的减少还与肾小球病理改变相关,足细胞融合、微绒毛化改变较多,肾小球硬化数明显增多。结论:糖尿病大鼠表现出肾小球足细胞数目及其密度的减少,肾小球足细胞中nephrin、desmin的表达和分布的减少,足细胞病变不仅导致大量白蛋白尿的发生,而且还与肾小球硬化和肾功能损伤的发生有关。缬沙坦联合苯那普利与单独用药治疗相比,较ACEI、ARB单独应用有更好的减轻足细胞损伤,起到肾脏保护作用。
Objective: To investigate the effects of valsartan combined with benazepril on podocyte injury in diabetic rats and its protective mechanism. Methods: SD rats were randomly divided into normal control group (group A), diabetic control group (group B), diabetic benazepril treatment group (group C), diabetic valsartan treatment group (group D) Tan combined Benazepril (Group E). The mean arterial pressure, blood glucose, serum creatinine, urinary creatinine, renal weight / body weight and urinary albumin excretion rate were measured at the end of the 4th and 6th week of the experiment in each group, and the kidney specimens were observed by light microscope and electron microscope. The average glomerular cross-sectional area and average glomerular volume of each group were measured by image analyzer. At the end of 6th week, the expression of TGF-β1 mRNA in renal cortex was detected by reverse transcription-polymerase chain reaction (RT-PCR). The podocyte specific markers nephrin and desmin were examined by immunohistochemical staining. The podocyte was accurately located and its density was observed quantitatively. The clinical and renal pathological parameters were also analyzed. Results: Beconazole, valsartan and valsartan combined with benazepril decreased Ccr, renal weight / body weight, urinary albumin excretion and TGF-β1 mRNA expression, while valsartan combined with benazepril Lee group on the TGF-β1 mRNA maximum inhibition, while renal pathological changes are the lightest. Group B, E group with glomerular podocyte number and density decreased, of which the most significant group B, C group, D group followed by the lightest. There was a significant negative correlation between the number of podocytes and their density and urinary protein (P <0.01). nephrin, desmin in group A along the glomerular basement membrane was continuous and linear distribution. The expressions of nephrin and desmin in group C, group D and group E were lower than those in normal tissue, and the expression of nephrin and desmin in group B was somewhat dotted and short-strip. Compared with normal tissue, the expression of nephrin and desmin was not statistically significant (P <0.05). Decreased number of podocytes in diabetic rats was also associated with pathological changes of glomerulus, podocyte fusion, microvilliification more changes, glomerular sclerosis increased significantly. CONCLUSIONS: Diabetic rats exhibit decreased numbers and density of glomerular podocytes, reduced expression and distribution of nephrin and desmin in glomerular podocytes, and podocytic lesions not only result in the development of extensive albuminuria, but also with Glomerulosclerosis and renal damage related to the occurrence. Compared with single drug treatment, valsartan combined with benazepril, compared with ACEI and ARB alone, could better reduce podocyte injury and play a protective role in the kidney.