醛固酮在腹膜透析大鼠腹膜纤维化中的作用

摘要

AIM:To investigate the pathologic role of aldosterone and protective effect of aldosterone receptor antagonist on peritoneal fibrosis in peritoneal dialysis rats .METHODS:A peritoneal fibrosis rat model was established by intraperitoneal injection of lipopolysaccharide ( at 1 d, 3 d, 5 d and 7 d, 0.6 mg/kg) and dialysate ( daily intraperitoneal injection of 4.25%dialysate, 100 mL/kg).At the same time, spironolactone (an aldosterone receptor antagonist , 100 mg・ kg -1・ d-1 ) was given to the model rats .After 4 weeks, the expression of aldosterone synthase CYP 11B2, 11β-hydrox-ysteroid dehydrogenase type 2 (11β-HSD2), mineralocorticoid receptor (MCR), and inflammatory factors were detected by immunohistochemistry , real-time PCR and Western blotting .RESULTS:The rat model of peritoneal fibrosis was suc-cessfully established .At the same time, the injury of mesothelial cells , deposition of collagen fibers and thickness of perito-neal were increased .Moreover , the infiltration of macrophages in the peritoneum/dialysate was increased .The level of al-dosterone and the expression of MCR , 11β-HSD2 and CYP11B2 in fibrotic peritoneum were obviously up-regulated as com-pared with normal rats .The expression of NF-κB/MCP-1 was also increased .However , treatment with spironolactone alle-viated peritoneal fibrosis and reduced the expression of NF-κB/MCP-1.CONCLUSION:Local aldosterone is involved in the process of peritoneal fibrosis via NF-κB/MCP-1 pathway.Spironolactone alleviates peritoneal fibrosis of peritoneal dial-ysis.%目的：研究醛固酮在腹膜透析大鼠腹膜纤维化中的作用，以及醛固酮受体拮抗剂是否能够减轻腹膜纤维化。方法：通过腹腔注射脂多糖（第1、3、5、7天，0．6 mg／kg）＋透析液（每天腹腔注射4．25％含糖透析液100 mL／kg ）建立伴有腹膜纤维化的腹膜透析大鼠模型。同时给予醛固酮受体拮抗剂（螺内酯，100 mg・ kg－1・d－1）灌胃。4周后取大鼠腹膜行病理和免疫组化检测，同时采用real－time PCR和Western blot法检测醛固酮合成酶（CYP11B2）、11β－羟基类固醇脱氢酶2型（11β－HSD2）、盐皮质激素受体（MCR）和炎症因子的表达情况。结果：成功建立伴有腹膜纤维化的腹膜透析大鼠模型，发现腹膜间皮细胞受损，形态改变，胶原纤维沉积，腹膜增厚，腹膜和腹透液中巨噬细胞浸润增多。与正常大鼠相比，腹膜上MCR、11β－HSD2和CYP11 B2表达增高，醛固酮含量增多。同时腹膜上NF－κB／MCP－1表达增加。而给予螺内酯治疗后腹膜纤维化减轻，NF－κB／MCP－1表达减少。结论：局部产生的醛固酮可能通过NF－κB／MCP－1途径参与腹膜纤维化过程。醛固酮受体拮抗剂螺内酯能够减轻腹膜透析大鼠的腹膜纤维化程度。