急性肾损伤（AKI）是常见的危急重症，尚无有效治疗药物。血小板参与了炎症过程，且在缺血再灌注AKI中，使用其抑制药氯吡格雷可减轻肾损伤，但血小板如何参与AKI？其具体作用和机制尚不清楚。我们预实验发现，AKI（包括2种动物模型及病人）血小板功能和颗粒释放增强，膜受体GPVI表达增高。我们推测，肾小管上皮细胞损伤后释放的物质增加了血小板GPVI表达与活化，引起血小板颗粒释放，促进肾间质炎性细胞浸润，继而加速肾小管上皮细胞损伤，形成“上皮细胞损伤-血小板GPVI活化”的恶性循环。该研究拟以体外细胞实验和体内动物实验，运用组织病理、生化检测、血小板功能实验、RT-PCR、蛋白印迹、染色质免疫共沉淀技术及蛋白质组学等方法，并利用GPVI基因敲除小鼠，研究AKI血小板膜受体GPVI表达上调机制及其促进急性肾损伤的作用和机制，确证干预GPVI阻断该恶性循环，减轻肾损伤，为AKI防治提供新途径。

Acute kidney injury (AKI) is a common clinical severe disease, which there is no effective treatment by now. Platelets are involved in process of inflammation. It has been reported that, in the acute kidney injury caused by ischemia-reperfusion, anti-platelet agent clopidogrel alleviates kidney injury. However, how do platelets participate in acute kidney injury in detail? And its specific role and mechanism are still unclear. Our preliminary data implied that platelet activity, granule release and membrane receptor GPVI expression were increased in acute kidney injury (including two kinds of AKI animal models and patients). Therefore, we hypothesize that there is an "epithelial cell injury - platelet GPVI activation" vicious circle in AKI. As substances released from damaged tubular epithelial cell increase platelet GPVI expression and activation, causing release of platelet granules, leading to perivascular capillary endothelial cell damage, promoting renal interstitial infiltration of inflammatory cells, and these accelerate renal tubular epithelial cells injury. The project will involve both cell and animal experiments, using histopathology, biochemical tests, platelet function tests, RT-PCR, Western blotting, Chromatin Immunoprecipitation, flow cytometry and proteomics methods and GPVI knockout mice to study the mechanism of up-regulation of platelet membrane receptor GPVI expression in acute kidney injury and its role and mechanism in promoting acute kidney injury. The grant will confirm that the intervention of GPVI block the vicious circle, reduce renal damage, and find new targets for prevention and treatment of acute kidney injury.