CXCR4/AT1信号轴影响肾足细胞与系膜细胞交流的调控机制研究

肾小球损伤以肾小球滤过屏障受损和系膜基质扩张为特征，这一表现主要由足细胞损伤和系膜细胞活化引起。但是两者相互交流的潜在机制鲜少报道。我们前期发现在肾小球疾病中，趋化因子受体CXCR4特异性高表达于足细胞，其配体SDF-1α特异性高表达于系膜细胞并可靶向足细胞诱导足细胞损伤；我们进一步发现足细胞中CXCR4的上调伴随着血管紧张素II(AngII)的产生，而其受体AT1高表达于系膜细胞。据此我们提出：足细胞损伤早期可致CXCR4表达上调并合成大量AngII,AngII可通过旁分泌作用于系膜细胞并与其配体AT1结合引起系膜细胞活化及合成大量SDF-1α,SDF-1α可进一步作用于足细胞加重足细胞损伤。本项目拟通过构建足细胞特异性CXCR4基因敲除小鼠并采用足细胞和系膜细胞系，深入探索CXCR4/AT1信号轴促进肾小球损伤的致病机制。本项目为肾小球疾病的致病机制提供新的理论依据及新的干预靶点。

Glomerular injury is characterized by the deficiency of glomerular filtration barrier and expansion of mesangial matrix, which mainly results from podocyte injury and mesangial cell activation. However, the underlying mechanisms of crosstalk between podocyte and mesangial cell are rarely reported. Previously, we found that the expression of CXCR4 in glomerular diseases was progressively upregulated, and especially in podocytes. While its ligand SDF-1α was primarily upregulated in mesangial cells and further triggered podocyte injury. We then found that the upregulation of CXCR4 in podocytes was accompanied by the production of AngiotensinII(AngII), while its receptor type 1 angiotensin receptor （AT1） was primarily upregulated in mesangial cells. Based on our previous studies, we hypothesize that podocyte CXCR4 could be upregulated in the early stage of podocyte injury and further lead to the secretion of AngII. AngII could bind to AT1 receptor and trigger mesangial cell activation in a paracrine manner. Meanwhile, SDF-1α is produced in mesangial cell, then is secreted to podocyte and binds to CXCR4 to aggravate podocyte injury. In this study, we will explore the pathogenic mechanism by which CXCR4/AT1 axis promotes glomerular injury in vivo and vitro by adopting podocyte-specific CXCR4 knockout mice,podocyte and mesangial cell lines. This study provides a new theoretical basis for the pathogenic mechanism of glomerular diseases and a novel target of intervention for glomerular diseases.