氧化修饰蛋白影响肾足细胞和系膜细胞交流的调控机制研究

The cell-cell communication between renal podocytes and mesangial cells plays a key role in modulation of stability of glomerular structure and prevention of albuminuria. The recent study of applicant indicated advanced oxidation protein products (AOPPs), that extraordinarily upregulated in diabetes and other kidney diseases could induce podocyte apoptosis and damage silt diagram in vitro and vivo, trigger oxidative stress in mesangial cells, accelerate deterioration of glomerular function and development of albuminuria to proteinuria. It is intriguing to speculate AOPPs affect both cells and concomitantly, exert a major function in modulation of the cell-cell communication between podocytes and mesangial cells. Of note, the involving mechanisms of AOPPs in this process have not been elucidated. In this study, we will adopt podocyte and mesangial cell lines, diabetic rats and transgenic mice models to research the effects of AOPPs in cell-cell communication and demonstrate the mechanisms of modulation. The project intends to clarify the mechanisms of glomerular damage and provide a new theoretical basis for the pathogenic mechanism of AOPPs, in order to develop new ways of intervention.

足细胞和系膜细胞是肾小球内的固有细胞，两者相互协作交流的功能对维持肾小球结构稳定、防止蛋白尿发生具有关键作用。申请人和项目组新近研究结果表明糖尿病等肾脏疾病时异常增高的氧化修饰蛋白作为内源性致病物质诱导体内外模型的足细胞凋亡及裂孔蛋白表达下调、系膜细胞氧化应激和功能紊乱、肾小球功能下降和蛋白尿发生。提示氧化修饰蛋白在足细胞和系膜系膜细胞的细胞交流机制中占有重要地位。但是氧化修饰蛋白通过何种机制影响了足细胞和系膜细胞之间的交流目前国内外无报道。为进一步明确机制，本项目拟采用足细胞和系膜细胞系、糖尿病大鼠和转基因小鼠模型，深入研究氧化修饰蛋白影响足细胞和系膜细胞交流的调控机制，进一步阐明氧化修饰蛋白诱导肾小球损伤的机制；并明确氧化修饰蛋白损害细胞间相互交流功能的病理效应和调控机制，进而阐明氧化修饰蛋白导致肾小球固有细胞病变的分子机制，为氧化修饰蛋白的致病机制提供新的理论依据并发展新的干预途径。

氧化修饰蛋白通过何种机制影响了足细胞和系膜细胞之间的交流目前国内外无报道。我们研究发现趋化因子CXCL12受体CXCR4在氧化应激诱导的足细胞损伤中具有重要作用。主要结果如下: 1.CXCR4在损伤足细胞表达明显增加；2.氧化应激通过激活NADPH氧化酶/ERK/p65 NF-κB/CXCR4诱导足细胞损伤；3.CXCR4受体抑制剂明显减轻氧化应激诱导的足细胞损伤。此外，我们也发现了CXCR4-RAS信号轴介导了足细胞与系膜细胞之间的交流。该研究结果为氧化修饰蛋白的致病机制提供新的理论依据并发展新的干预途径。