TM5275对系膜细胞增殖与凋亡的影响及机制的研究

项目名称： TM5275对系膜细胞增殖与凋亡的影响及机制的研究

项目编号： No.81460150

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 黄文坛

作者单位： 广西壮族自治区人民医院

项目金额： 47万元

中文摘要： 系膜细胞（MC）相对性凋亡不足导致其异常增殖以及系膜基质增多是系膜增生性肾小球肾炎(MsPGN)进展的重要原因。纤溶酶原激活物抑制剂-1(PAI-1)具有抑制细胞外基质(ECM)降解、促进细胞增生和抑制其凋亡的作用,在各种急慢性肾损害肾脏中显著地表达，是强效的促肾纤维化因子。TM5275是新颖的PAI-1抑制剂，我们的研究表明其通过促进ECM的降解和诱导成纤维细胞的凋亡而抗肺纤维化，预试验表明TM5275可降低肾炎大鼠尿蛋白和系膜增生。由此推测其通过促进ECM的降解、抑制MC增生和促进其凋亡而具有治疗MsPGN的潜在前景。我们将用TGF-β1诱导的MC纤维化增殖模型，观测TM5275对ECM、MC增殖和凋亡的影响。TM5275干预MsPGN动物模型后，观察肾脏病理改变，TM5275对肾组织细胞凋亡和ECM的影响。通过体内外实验为TM5275应用于临床治疗慢性肾脏病提供理论依据。

中文关键词： 纤溶酶原激活物抑制剂-1；系膜细胞；增殖；凋亡；纤维化

英文摘要： The abnormal proliferation of mesangial cells (MC) caused by the relative lack of apoptosis and the increase of mesangial matrix are the important reasons for the lesion aggravation of Mesangial proliferative glomerulonephritis (MsPGN). Plasminogen activator inhibitor-1 (PAI-1) can inhibit ECM degradation, promote cell proliferation and inhibit apoptosis. As PAI-1 significantly expresses itself in many kinds of acute or chronic kidney damage, it is a potent fibrosis factor for kidney. TM5275 is a novel PAI-1 inhibitor. Our research shows that by promoting the degradation of ECM and the induction of apoptosis of fibroblast, TM5275 can effectively prevent pulmonary fibrosis. Preliminary experiments show that TM5275 can reduce urinary protein and mesangial proliferation on nephritis rats. Thus we speculate the potential prospects that by promoting the degradation of ECM, inhibiting MC proliferation and enhancing apoptosis, TM5275 can have a great effect on the treatment of MsPGN. In this study, by the model of MC fibrosis and proliferation induced by TGF - beta 1, we observe the effect of TM5275 on MC proliferation and apoptosis, and ECM. After the intervention of the animal MsPGN models with TM5275, we observe the pathological changes of the kidney and the effect of TM 5275 on tissue cell apoptosis and the change of ECM. Through these vitro and vivo experiments, we can explore the effect of TM5275 on mesangial cell proliferation and apoptosis and its regulatory mechanism, which is expected to provide evidences for the application of TM5275 to the treatment of chronic kidney diseases.

英文关键词： Plasminogen activator inhibitor-1;Mesangial cell;Proliferation;Apoptosis;Fibrosis