交感神经调控巨噬细胞活化状态在肾间质纤维化中的作用和机制研究

交感神经异常激活参与慢性肾脏病进展，而肾组织内巨噬细胞亚型活化则与肾纤维化密切相关。β2肾上腺素受体(β2AR)是G蛋白偶联受体，可与作用相反的激活型和抑制型G蛋白(Gs和Gi)结合。有研究表明：β2AR可介导巨噬细胞M2型活化。申请者前期在体研究证实：肾去神经术可减轻巨噬细胞浸润和纤维化程度；巨噬细胞Gs信号通路参与介导肾脏局部炎症微环境形成和纤维化进展。由此我们提出：在慢性肾脏病进程中，β2AR-Gs介导的M2型巨噬细胞活化是肾交感神经调控肾间质纤维化进展的重要机制，而Gs/Gi信号转换参与巨噬细胞亚型活化的调控。本项目拟从临床、动物、细胞三个层面，结合基因工程小鼠技术，阐明β2AR-Gs信号介导的M2型巨噬细胞活化在肾间质纤维化中的作用，探讨Gs/Gi信号的转换在纤维化不同阶段对巨噬细胞亚型活化的调控，为从神经-免疫调控角度出发探索肾纤维化精准治疗新策略提供实验依据。

Renal sympathetic nerve over-activation is involved in the progression of chronic kidney disease. Meanwhile, macrophage polarization is closely related to renal fibrosis. β2 adrenergic receptor (β2AR), a kind of G-protein coupled receptor, can be combined with stimulatory or inhibitory G protein (Gs or Gi) with opposite effects. It was reported that β2AR mediated the activation of alternatively activated macrophages (M2). Our preliminary data showed that denervation reduced the infiltration of macrophages and renal fibrosis in vivo, and Gs signaling in macrophages was involved in the development of renal inflammatory microenvironment and renal fibrosis. Therefore, we hypothesized that in the progression of chronic kidney disease, β2AR-Gs-mediated activation of M2 macrophages is the important mechanism for sympathetic nerves regulating the progression of renal interstitial fibrosis. And the signal switch between Gs and Gi participates in functional regulation of macrophages of different subtype. This project will try to clarify the mechanisms of M2 macrophage activation regulated by sympathetic nerve through β2AR-Gs signaling and the regulatory effects of Gs/Gi Coupling in renal fibrosis, which will provide the experimental evidence for the new therapeutic strategies of neuro-immunodolation.