促红细胞生成素通过BMP/SMAD通路对肾性贫血大鼠肾脏的保护作用及其机制  

Renoprotective action by erythropoietin via BMP/SMAD signaling pathway in renal anemia in rats and its mechanism

作　　者：张妍[1] 李银岚[1] 陈孟华[1] 

机构地区：[1]宁夏医科大学第二附属医院肾脏内科,宁夏银川750001

出　　处：《西安交通大学学报（医学版）》2015年第6期765-769,800,共6页Journal of Xi’an Jiaotong University（Medical Sciences）

基　　金：宁夏自然科学基金资助项目(No.NZ13202);宁夏医科大学科学研究基金资助项目(No.XM2012036)~~

摘　　要：目的探讨促红细胞生成素(EPO)对肾性贫血大鼠肾脏的保护作用及其可能的作用机制。方法将实验大鼠随机分为对照组(NC组,n=18)和实验组(n=72),采用腺嘌呤注射建立肾性贫血大鼠模型,再随机分为单纯贫血组(SA组)、铁剂+促红素组(IR+EPO组)、促红素组(EPO组)、铁剂组(IR组)。药物干预4周后,处死大鼠(心脏取血),自动化血液分析仪检测血清肌酐(Scr)、尿素氮(Bun)、血红蛋白(Hb)、血细胞比容(Hct);ELISA法检测铁调素(Hepcidin)。免疫组织化学染色法和Western blot法分别检测大鼠肾脏骨形态蛋白-6(BMP-6)、丝/苏氨酸激酶受体-1(SMAD-1)和SMAD-4的表达。结果 1一般指标的比较:与SA组相比较,IR+EPO组和EPO组BUN、Scr显著降低(P<0.01);IR+EPO组和EPO组Hb、Hct显著升高(P<0.01)。2ELISA法检测示IR+EPO组和EPO组铁调素显著降低(P<0.01)。3病理学观察提示EPO可以减轻大鼠肾脏病理及功能改变。4免疫组织化学染色示各组大鼠肾小球细胞胞质和肾小管上皮细胞内均表达SMAD-4、SMAD-1、BMP-6。5Western blot进一步提示,与SA组相比,IR+EPO组和EPO组SMAD-4蛋白表达量显著下调(P<0.01),IR+EPO组和EPO组SMAD-1蛋白表达量下调(P<0.05),IR+EPO组和EPO组BMP-6蛋白表达量显著上调(P<0.01)。结论 EPO通过BMP/SMAD传导通路,抑制铁调素的表达及分泌,纠正贫血,发挥肾脏保护作用。Objective To investigate the protective effect of erythropoietin（EPO）on the kidney of renal anemia rats and further explore the renoprotective action and possible mechanisms.Methods A total of 90 SD rats were randomly divided into5 groups：normal control rats（NC）,simple anemia group（SA）,iron＋ EPO group（IR＋EPO）,erythropoietin group（EPO）,and iron group（IR）with18in each.The rats were sacrificed after 4 weeks＇treatment with intragastrically-injected adenine.Serum creatinine（Scr）,blood urea nitrogen（Bun）,hemoglobin（Hb）,hematocrit（Hct）,and hepcidin were measured with automated hematology analyzer.The expressions of bone morphogenetic protein-6（BMP-6）,a serine/threonine kinase receptor-1（SMAD-1）and serine/threonine kinase receptor-4（SMAD-4）in the kidney were detected by immunohistochemistry and Western blot.Results 1The results of general indicators：BUN and Scr in IR ＋ EPO group and EPO group were lower than those in SA group（P〈0.01）.Hb and Hct in IR ＋ EPO group and EPO group were increased significantly compared with those in SA group（P〈0.01）.Hepcidin was significantly increased in simple anemia group（P〈0.01）.2 ELISA results showed that Hepcidin was lower in IR ＋ EPO group and EPO group than in SA group（P〈0.01）.3 The results of pathological observation indicated that EPO could reduce rat renal pathology and function.4Immunohistochemistry revealed that SMAD-4,SMAD-1 and BMP-6 were expressed in the rat glomerular cells and renal tubular epithelial cells.5 Western blot further indicated that the expression of SMAD-4 was significantly decreased in IR＋EPO group and EPO group（P〈0.01）.The expression of SMAD-1 in IR＋EPO group and EPO group was decreased（P〈0.05）while that of BMP-6 was elevated in IR＋EPO group and EPO group（P〈0.01）.Conclusion The expression and secretion of hepcidin were inhibited by EPO via the BMP/SMAD pathway,which further corrects anemia and exerts a renal protective effect.

关 键 词：肾性贫血 促红细胞生成素 BMP/SMAD 铁调素 骨形态蛋白-6(BMP-6) 

分 类 号：R556[医药卫生—血液循环系统疾病]