替米沙坦上调肝细胞生长因子表达的分子机制研究

目的探讨替米沙坦对肝细胞生长因子（hepatocyte growth factor, HGF）表达的影响及其机制研究。方法选取体外培养大鼠肾系膜细胞，观察不同浓度（0．1μmol／L、1．0μmol／L、10．0μmol／L）替米沙坦干预24h对HGF表达的影响；采用双荧光素酶报告基因分析系统检测HGF启动子活性和替米沙坦的PPAR7反应性。非放射性蛋白激酶检测系统及Westernblot检测PKA、CREB、pCREB蛋白表达。结果与正常对照组相比，替米沙坦能明显增加HGF蛋白表达，该作用呈浓度依赖性（P〈0．05）；荧光素酶检测证实HGF基因的-290／＋20序列存在潜在PPAR7反应元件，10μmol／L替米沙坦显著增强HGF启动子活性（P〈0．05）。同时蛋白检测提示替米沙坦抑制系膜细胞PKA活性，下调pCREB蛋白表达。结论替米沙坦上调HGF表达独立于PKA／CREB信号通路，可能通过结合HGF启动子PPAR7反应元件上调HGF表达。

Research on molecular mechanism of hepatocyte growth factor upregulation induced by telmisartan

Objective To observe the influence of telmisartan on hepatocyte growth factor expression and the probable mechanisms. Methods After stimulation with different concentrations of telmisartan for 24 h,the expression of HGF was detected by using ELISA. The luciferase assays with Promega assay sys- tems were used for detection of PPAR7 activation and HGF promotor. The expression of PKA, CREB and pCREB was examined by using PepTag Non-Radioactive Protein Kinase Assays and Western blotting. Results Telmisartan could increase the expression of HGF mRNA and protein in a dose-dependem manner （P〈0.05）. HGF gene - 290/＋ 20 sequence had potential PPRE and exhibited promotor activity. After stimula- tion with 10 banol/L telmisartan, the HGF promotor activity was significantly increased （P〈0. 05）. However, the activation of PKA/CREB/pCREB pathway was inhibited by telmisartan. Condusiom Telmisartan could increase the HGF expression. The upregulation of HGF was induced by HGF promotor activation, which was independent of PKAJCREB pathway.