C3a/C3aR轴过度活化在糖尿病肾病中的作用及机制研究

项目名称： C3a/C3aR轴过度活化在糖尿病肾病中的作用及机制研究

项目编号： No.81370828

项目类型： 面上项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 郑敬民

作者单位： 中国人民解放军东部战区总医院

项目金额： 70万元

中文摘要： 越来越多的证据表明：糖尿病肾病（DN）是一种慢性炎症疾病，补体活化参与了DN病理过程。但有关DN炎症机制和补体系统参与DN的具体机制仍不是很清楚。在前期研究中，我们发现：补体活化产物C3a的受体C3aR在DN患者和模型动物肾组织中的表达显著上调，DN肾组织存在C3a/C3aR过度活化的情况；从C3aR的分布及相关性分析来看，C3a/C3aR过度活化很可能在DN炎症、肾小管和足细胞损伤中有重要作用。本项目拟在已有研究基础上，利用临床观察、动物实验和体外细胞实验相结合，采用C3aR激动剂和拮抗剂干预，以及转基因动物等手段对C3a/C3aR过度活化在DN中的具体作用（特别是在DN炎症、小管和足细胞损伤中的作用）和可能机制进行研究，以阐明C3a/C3aR在DN中的病理意义，增加对DN炎症机制和补体系统参与DN机制的认识，了解C3a/C3aR能否作为DN防治的新靶标，最终为提高DN诊疗水平创造条件。

中文关键词： C3a;C3aR;糖尿病肾病;;

英文摘要： Studies in recent years have demonstrated that diabetic nephropathy (DN) is a chronic inflammatory renal disease. The complement system has been found involved in the pathologic process of DN. However, the inflammatory mechanisms of DN and the mechanisms by which the complement system is involved in the disease are not clear. In preliminary studies, we found that C3aR, the receptor for C3a, was upregulated in both the kidney of patients with DN and the kidney of model animals, indicating that a situation of C3a/C3aR axis over-activation exists in DN. The increased C3aR was found distributed mainly in the tubular epithelial cells, glomerular parietal epithelial cells and podocytes. Significantly increased C3aR was often observed in the injured tubulus, detached podocytes, proliferating podocytes and parietal epithelial cells. Also, C3aR was found in the renal infiltrating cells. The increased expression of C3aR was found correlated with clinical index reflecting renal injury. These findings suggested that over-activation of C3a/C3aR axis might have important roles in DN, especially in tubular injury, podocytes injury and renal inflammation. The present items aim to clarity the pathological roles of C3a/C3aR in DN and to determine whether C3a/C3aR can be used as a target for treatment of DN. It will provide a new insight in renal inflammation mechanisms under DN condition and the mechanisms by which the complement system is involved in the disease. Also, the items will be helpful in developing new strategy for treatment of DN. To achieve these goals, patients at different stages of DN will be recruited, the expression changes of C3a and C3aR will be examined, and the correlation between C3a/C3aR axis and DN will be evaluated. In the mean while, db/db mice were used as a model and the influences of SB290157 (an antagonist for C3aR) and WWGKKYRASKLGLAR (an agonist for C3aR) on the initiation and development of DN will be evaluated. Further more, transgenic mice specifically express C3aR miRNA in tubular epithelial cells or in glomerular podocytes will be constructed and the difference between these mice and wild mice in the renal injury under diabetic conditions will be examined. In the in vitro studies, cell line HK-2 and HPC will be used as models to investigate the possible roles of C3a/C3aR axis in the injury of tubular epithelial cells and podocytes respectively. Also, these cell lines will be used to elucidate the signal pathway involved.

英文关键词： C3a;C3aR;diabetic nephropathy