Rho激酶和转化生长因子β通路在醛固酮/盐诱导的单肾切除SD大鼠肾脏损伤中的作用  

Role of Rho-kinase and TGF-β pathway in aldosterone/salt-induced renal injury in uninephrectimized SD rats

作　　者：孙广萍[1] 张锦[2] 刘东[3] 李德天[1] 

机构地区：[1]中国医科大学附属盛京医院肾内科,辽宁沈阳110004 [2]中国医科大学附属第一医院内分泌科,辽宁沈阳110001 [3]中国人民解放军空军总医院肾内科,北京100036

出　　处：《中国现代医学杂志》2008年第10期1388-1393,1398,共7页China Journal of Modern Medicine

基　　金：辽宁省教育厅基金;课题题目(抗动脉粥样硬化因子-高密度脂蛋白及其受体对抗动脉粥样硬化作用机制研究。No:04D159)

摘　　要：目的观察Rho激酶和转化生长因子β(transforming growth factor-β,TGF-β)通路是否参与醛固酮/氯化钠诱导的单肾切除SD大鼠肾脏损伤的发病及可能的机制。方法健康雄性5周龄SD大鼠在实验初始行右肾切除,手术后2周给予1%氯化钠饮水。随机将大鼠分3组:对照组(2%酒精皮下泵入,n=9);醛固酮组(2%酒精+醛固酮0.75μg/H皮下泵入,n=9);醛固酮+fasudil组[2%酒精+醛固酮0.75μg/H皮下泵入+fasudil 10mg/(kg·day)皮下注射,n=8]。共治疗5周。观察收缩压、尿蛋白、肾功能、肾组织学改变,并用western blot法和real-time PCR法观察肾皮质磷酸化MYPT1(代表Rho激酶活性)和Smad2/3蛋白表达和TGF-β1、结缔组织生长因子(connective tissue growth factor,CTGF) mRNA表达。结果醛固酮/盐长期灌注引起渐进性高血压同时伴有以大量蛋白尿,肌酐清除率下降,严重的肾小球增生和硬化、间质纤维化为特征的肾脏损伤,同时伴有肾皮质磷酸化MYPT1和Smad2/3表达增加,TGF-β1、CTGF mRNA表达增高。fasudil治疗在抑制Rho激酶活性的同时,虽未有降压作用,却明显减轻了肾脏损伤,减少了磷酸化Smad2/3蛋白及TGF-β1、CTGF mRNA表达。结论Rho激酶通过活化TGF-β1-Smad2/3-CTGF信号通路参与了醛固酮/盐持续灌注单肾切除SD大鼠的肾脏损伤。[Objective] To investigate the potential contributions of Rho-kinase and transforming growth factor （ （TGF-β） pathways to Aldosterone/salt-induced renal injury in uninephrectomized SD rats. [Methods] 26 SD rats were uninephrectomized and then treated for 5 weeks with 1%NaCl in a drinking solution and one of the following： vehicle （2% Ethanol, SC, n =9）; Aldosterone （2% Ethanol＋0.75 μg/H, SC, n =9）; Aldosterone（2% Ethanol＋0.75μg/H, SC） ＋ fasudil, a specific Rho-kinase inhibitor [10 mg/（kg·d）, SC, n =8]. Systolic blood pressure（SBP）, urinary protein volume, renal function and renal morphologic changes were all observed. And phosphorylated of myosin phosphate target subunit-1 （MYPT1）which represents Rho-kinase actitivity, Smad2/3 phosphorylation , as well as mRNA expressions of TGF-β, connective tissue growth factor（CTGF） in renal cortical tissue were all measured respectively by Westernblot and real-time PCR. [Results] Aldosterone-infused rats exhibited hypertension and severe renal injury characterized by proteinuria, glomerular sclerosis and tubulointerstitial fibrosis. Renal cortical mRNA levels of TGF-β and CTGF, as well as Smad2/3 phosphorylation were significantly increased in aldosterone-infused rats. All these changes were associated with an increase in renal tissue MYPT1 phosphorylation. Treatment with fasudil did not alter blood pressure, but significantly ameliorated proteinuria and renal injury in Aldosterone-infused rats. Furthermore, fasudil prevented MYPT1 phosphorylation and markedly decreased mRNA levels of TGF-β and CTGF and Smad2/3 activity in renal cortical tissues. [Conclution] These results provide evidence, for the first time, that Rho-kinase is substantially involved in Aldosterone-induced renal injury through activation of TGF-β-dependent pathway.

关 键 词：醛固酮 肾脏损伤 RHO激酶 TGF-β 

分 类 号：R692[医药卫生—泌尿科学]