FGL2促Gal-3表达介导肾间质纤维化的作用及机制研究

Renal interstitial fibrosis （RIF）is widely regard as the common pathway of CKD progression to ESRD, without effective treatment strategies except for renal replacement therapy. It was believed that immune inflammatory response plays an important role in RIF development and process, but the underlying mechanism remains unclear. Moreover, several studies indicated that FGL2 plays a pivotal role in regulating inflammatory response. In the previous studies, we found that FGL2 expression were significantly up-regulated in fibrotic renal from CKD patients and RIF mouse model. On the contrary, RIF and Gal-3 expression attenuated dramatically in FGL2 gene knock-out mice. Gal-3 has been proved to be an essential fibrotic promotor. We therefore hypothesized that FGL2 mediates the RIF initiation and progression via promoting Gal-3 expression. In this study, the effects and underlying mechanisms of FGL2 mediates RIF via enhancing Gal-3 expression will be deeply investigated. Anticipative results will enhance our knowledge for the pathophysiology mechanisms of in RIF, which ultimately provide effective treatment strategies for RIF.

肾间质纤维化是各种慢性肾病向终末期肾病进展的共同通路，也是导致肾功能逐渐丧失的主要因素。除肾脏替代疗法外，目前尚无有效治疗手段。免疫炎症反应在肾间质纤维化病理过程中扮演着重要角色。作为一种重要的炎症调节因子，我们的前期研究首次发现：FGL2在慢性肾病患者及肾间质纤维化小鼠肾组织中表达显著增加；FGL2基因敲除后肾间质纤维化明显减轻，且促纤维化因子Gal-3的表达显著下调。据此我们推测：FGL2可能通过促Gal-3表达介导肾间质纤维化的发生发展。本研究拟在前期预实验基础上，通过体内外实验进一步明确FGL2在肾间质纤维化中的重要作用，探讨FGL2促Gal-3表达介导肾间质纤维化分子机制。预期实验结果可加深对肾间质纤维化病理发生机制的认识，为其临床治疗新策略发展提供重要理论依据。

肾间质纤维化(RIF)是各种慢性肾病向终末期肾病进展的共同通路，也是导致肾功能逐渐丧失的主要因素。除肾脏替代疗法外，目前尚无有效治疗手段。免疫炎症反应在肾间质纤维化病理过程中扮演重要角色。作为一种重要炎症负调因子，FGL2在肾间质纤维化病理过程中的作用尚不明确。本项目研究结合生物信息技术、临床肾穿刺标本及动物实验发现：肾间质纤维化病理过程中FGL2表达显著上调；运用FGL2基因敲除及外源性补充FGL2蛋白两种手段，从正反两个方面明确了FGL2抑制UUO诱导肾间质纤维化病理过程，并发现其机制可能与FGL2抑制STAT6磷酸化衰减M2型巨噬细胞极化有关。在FA构建的急慢性肾损伤模型中发现：FGL2基因敲除后FA诱导的急慢性肾损伤明显加重，超微电镜发现线粒体损伤加重，GPX4表达显著下调，表明FGL2可能通过抑制肾小管细胞铁死亡减轻FA诱导肾损伤。此外，在IRI-RIF模型中，FGL2敲除后肾间质纤维化明显加重，其机制尚需进一步研究。本项目从新型凝血分子FGL2免疫调节功能的视角解析其抑制肾间质纤维化的重要作用及机制，预期实验结果可加深对肾间质纤维化病理发生机制的认识，为其临床治疗新策略发展提供重要理论依据。现已发表SCI论著4篇，中文期刊2篇, 获批实用新型专利3项。资助培养硕士研究生1名。