M2巨噬细胞表达Legumain促进肾间质纤维化损伤修复的机理及应用研究

Renal interstitial fibrosis is the common pathological feature of the unsolving chronic renal diseases, no matter what the cause of illness are. It is still controversial the beneficial effect of macrphages on the renal fibrosis although it has been proven that M2 macrophages are able to alleviate the level of renal injury in varied animal models of renal diseases. .Our preliminary data suggest that increased Legumain expression accompanied with the increased amount of M2 macrophages during the progress of renal fibrosis; M2 macrophages express and secret Legumain;legumain accelerates the degradation of Fibronetin, the major component of extrcellular matrix. Given all these results from our lab as well as several important data from others' experiments, we hypothesize a novel and lymphocyte independent mechanism mediating the repair of renal interstitial fibrosis: legumain expressed and secreted by M2 macrophages promotes the degradation of extracellular matrix and collagen. In this project, we will explore that whether the anti-fibrosis effect of M2 macrophage depend on Legumain; and evaluate whether inducing M2 macrophages and thus increasing expression of legumain also mediate the renal beneficial effect of late administration of Vitamin D.In addition, we will construct the macrophages with stable overexpression of Legumain and test its therapeutic effect on the renal interstitial fibrosis in animal models. .Our study will help understanding the mechanism underlying the interaction between inflammation and fibrosis comprehensively; of more importance, our study sheds new light on the treatment of renal fibrosis.

肾间质纤维化是各种原因慢性肾病持续发展至终末期共同的病理表现。炎症与纤维化关系密切，阐明其机制对肾间质纤维化的治疗至关重要。本项目前期研究结果表明，肾间质纤维化发展过程中M2巨噬细胞比例增高的同时伴有Legumain表达水平上调；M2巨噬细胞能表达Legumain；体外实验中Legumain能降解细胞外基质成分Fibronectin。据此，我们提出一种新的、非淋巴细胞依赖的肾间质纤维化修复的假说，即巨噬细胞通过表达和分泌Legumain促进细胞外基质和胶原降解。本项目中我们将探索M2巨噬细胞对肾间质纤维化的作用与表达Legumain的关系；验证肾间质纤维化模型中晚期给予维生素D延缓纤维化进展的作用与激活M2巨噬细胞表达Legumain的关系；构建过表达Legumain的巨噬细胞并初步探索其治疗肾间质纤维化的效果。本研究结果有助于全面了解炎症与肾间质纤维化的关系，并为治疗提供新的思路。

肾间质纤维化是各种原因慢性肾病持续发展至终末期共同的病理表现。炎症与纤维化关系对阐明肾间质纤维化发病机制至关重要。本项目旨在探索M2巨噬细胞通过过表达Legumain抑制肾间质纤维化的机理，并初步探索其治疗应用。主要研究内容包括：I. 明确Legumain 表达上调与M2 巨噬细胞减轻肾间质纤维化损伤的关系；II 明确纤维化中晚期给予维生素D 减轻肾间质纤维化损害作用与M2 巨噬细胞的关系；III探索输注过表达Legumain 的巨噬细胞作为肾间质纤维化治疗手段。通过项目的研究，我们明确了Legumain 表达上调与M2 巨噬细胞减轻肾间质纤维化损伤作用的关系：明确M2巨噬细胞表达并分泌legumain进而促进细胞外机制降解的机制；探讨了维生素D减轻肾间质纤维化的作用与激活M2巨噬细胞表达和分泌legumain的关系，并进行了输注过表达legumain的单核细胞治疗肾间质纤维化的探索。研究结果表明，肾间质纤维化发展的过程中，M2型巨噬细胞通过表达legumain，并由外泌体递送到细胞外基质，行使降解主要细胞基质成分Fibronectin以及Collagen的作用，从而抑制纤维化的进展并促进纤维化过程的修复。通过输注表达legumain的单核细胞能够有效减轻肾间质纤维化的损伤。.本项目共发表带标注论文SCI论文4篇。培养硕士毕业生2名，博士毕业生3名。