Ang-(1-7)及其受体调控缓激肽系统对糖尿病肾病足细胞损伤的影响及机制研究

项目名称： Ang-(1-7)及其受体调控缓激肽系统对糖尿病肾病足细胞损伤的影响及机制研究

项目编号： No.81500550

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 陈桂香

作者单位： 上海交通大学

项目金额： 18万元

中文摘要： 足细胞损伤致蛋白尿是糖尿病肾病（DN）进展的关键。RAS新成员Ang-(1-7)与其特异性的Mas受体结合而负性调控传统的RAS通路；缓激肽（BK）可防止DN足细胞丢失；而Ang-(1-7)可增加BK，并在BK的作用下改善糖代谢。我们前期研究已证实足细胞上MasR的存在；据此推测Ang-(1-7)与MasR结合，可能上调BK的表达，使BK受体结合增加，游离BK受体减少，进而拮抗Ang Ⅱ- ACE-AT1R 轴，减轻足细胞损伤，延缓DN进展。本课题首次探讨了Ang(1-7)结合MasR调控BK及BK受体对DN足细胞损伤的影响及机制；拟通过临床病例分析循环Ang-(1-7)、BK与尿足细胞、蛋白尿的相关性；建立DN动物模型及体外培养高糖刺激的足细胞，予Ang-(1-7)、BK受体激动剂、阻滞剂等干预后观察BK、BK受体变化及足细胞损伤并探讨其调控机制，为DN的诊治及新药物开发提供新的策略。

中文关键词： 糖尿病肾病；足细胞损伤；肾素血管紧张素系统；缓激肽

英文摘要： Podocyte injury may lead to Proteinuria, which is the key cause of diabetic nephropathy(DN)’s continued progress. RAS new member Ang-(1-7) negatively regulated the traditional RAS pathway through combining with its specific Mas receptor (MasR). Bradykinin (BK) may prevent the podocyte loss in DN. Furthermore, Ang-(1-7) could increase the BK and ameliorate glycometabolism under the BK’s action. Our recent study had proved the existence of MasR in podocyte. On these grounds, we propose the hypothesis that Ang-(1-7) combining with MasR may up-regulate the BK expression, which make combined BK receptors increasing and then free BK receptors decreasing, thus antagonize the AngⅡ-ACE-AT1R axis, relieve podocyte injury and delay the DN progression. This investigation probes the effects of Ang-(1-7) and its Mas receptor regulating BK and BK receptor on podocyte injury in DN and its possible mechanisms for the first time. We will analyze the relevance of circulating Ang-(1-7), BK, urinary podocytes and protienuria through clinical cases; DN animal models will be established and podocyte will be cultured with high glucose in vitro, and then Ang-(1-7)、BK receptor agonist and antagonist will be used to interfere in order to observe the change of BK and BK receptor and podocyte injury. The study will further clarify the regulatory mechanisms and provide a new strategy for the treatment of DN and the development of the new drugs.

英文关键词： diabetic nephropathy;podocyte injury;renin angiotensin system;bradykinin