糖尿病肾病（DKD）发病机制尚不完全清楚。足细胞损伤是DKD发病的关键环节。中性粒细胞胞外网络（NETs）是一种以染色质为骨架，附着弹性蛋白酶、髓过氧化物酶等多种蛋白的中性粒细胞外网络状复合体，高血糖等因素可诱导其产生。课题组前期动物和细胞实验数据显示NETs与DKD足细胞损伤之间可能具有因果关系。本研究拟利用中性粒细胞PAD4基因敲除小鼠特异性抑制NETs产生，进一步阐明NETs在糖尿病足细胞损伤中的重要作用。鉴于滤过屏障的存在，NETs对足细胞的损伤可能存在间接和直接两种机制。在体外研究部分，我们将一方面从肾小球内皮细胞与足细胞相互作用的角度，重点探讨NETs是否通过增加肾小球内皮细胞分泌IL-1α，间接引起足细胞损伤。另一方面，我们将进一步从NETs主要成分与足细胞相互作用的角度，阐明NETs对足细胞的直接损伤。本研究结果对DKD的防治有重要意义。

The mechanism of Diabetic Kidney Disease (DKD) is not fully understood. Podocyte injury is key to the DKD incidence. Neutrophil Extracellular Traps (NETs) is a kind of neutrophils extracellular network complex, which is composed of chromatin as skeleton, and attached with elastase and peroxidase. NETs could be induced by hyperglycemia. Our preliminary data from cells and animals showed a potential causal relationship between NETs and DKD podocyte injury. This study is going to use PAD4 gene knockout mice to inhibit NETs formation, and further elucidate the key role of NETs in the DKD podocyte injury. As the existence of filter barrier, there may be indirect and direct mechanisms for the podocyte injury induced by NETs. In vitro, we will focus on the aspect of interaction between glomerular endothelial cells and podocyte, and we will demonstrate whether NETs could indirectly induce podocyte injury by increasing IL-1α of glomerular endothelial cells. On the other hand, we will clarify the direct podocyte injury induced by NETs from the aspect of interaction between the main components of NETs and podocyte. The results of this study might be of significance to the prevention and treatment of DKD.