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目的:观察螺内酯对糖尿病大鼠肾小管间质的保护作用并探讨其机制。方法:雄性SD大鼠,随机分为健康对照组、糖尿病组和螺内酯治疗组。8周后检测各组大鼠血压、24 h尿蛋白定量、血肌酐、血钾、血糖、内生肌酐清除率;留取肾组织作PAS染色行病理检查;采用免疫组织化学技术检测近端肾小管上皮细胞醛固酮受体(MR)、检测肾小管-间质中基质金属蛋白酶-2(MMP-2)及α-平滑肌肌动蛋白(-αSMA)表达,并做半定量分析。结果:各组大鼠肾脏近端小管上皮细胞胞质内均有MR表达,与健康对照组相比,糖尿病组近端小管MR表达上调,螺内酯对MR的表达无影响;糖尿病组大鼠肾小管间质MMP-2、-αSMA表达均显著高于对照组(P<0.01),螺内酯治疗8周后,肾组织MMP-2及-αSMA明显下调(P<0.01),肾功能指标及组织病理学损害得以改善,而螺内酯对大鼠的血压、血钾没有影响(P>0.05)。肾组织内-αSMA与MMP-2的表达具有明显的正相关关系(r=0.920,P<0.01)。结论:大鼠近端小管上皮细胞存在MR的表达,糖尿病肾内MR表达增加可能是醛固酮促肾纤维化的部分原因;螺内酯对糖尿病大鼠肾小管间质病变具有保护作用,其机制至少部分与抑制肾小管上皮-肌成纤维细胞转分化,下调肾小管间质中MMP-2、-αSMA表达有关。
Objective: To observe the protective effect of spironolactone on the tubulointerstitium in diabetic rats and its mechanism. Methods: Male SD rats were randomly divided into healthy control group, diabetic group and spironolactone treatment group. After 8 weeks, blood pressure, 24 h urinary protein, serum creatinine, serum potassium, blood glucose and endogenous creatinine clearance rate were measured in all groups. Renal tissues were collected for pathological examination by PAS staining. Immunohistochemistry The expression of matrix metalloproteinase-2 (MMP-2) and α-smooth muscle actin (-α SMA) in tubulointerstitium was detected by semiquantitative analysis of aldosterone receptor (MR) in tubule epithelial cells. Results: The expression of MR in the cytoplasm of renal proximal tubule epithelial cells in each group was higher than that in healthy control group. MR expression in proximal tubule of diabetic group was increased and spironolactone had no effect on MR expression. Compared with healthy control group, The expression of MMP-2 and -αSMA in the interstitium was significantly higher than that in the control group (P <0.01). After spironolactone treatment for 8 weeks, the expression of MMP-2 and -αSMA in renal tissue was significantly decreased (P <0.01), and renal function and histopathology Damage was improved, while spironolactone had no effect on blood pressure and potassium in rats (P> 0.05). There was a significant positive correlation between -αSMA and MMP-2 expression in renal tissues (r = 0.920, P <0.01). CONCLUSION: MR expression exists in proximal tubular epithelial cells of rats, and increased MR expression in diabetic nephropathy may be partly responsible for aldosterone-induced renal fibrosis. Spironolactone has a protective effect on tubulointerstitial lesions in diabetic rats, and its mechanism is at least partially related to Inhibition of renal tubular epithelial - myofibroblast transdifferentiation, down regulation of renal tubulointerstitial MMP-2, -αSMA expression.