AT1R-G蛋白/β-arrestins通路偏好性激活在急性肾损伤中的作用及其机制

急性肾损伤的发生率高、预后差，目前缺乏有效的干预策略。AT1R阻断药（ARBs）可以改善急性肾损伤，但也增加肾脏损伤风险。申请人拟筛选一类AT1R配体，既能保留ARBs的益处，同时减弱或去除其副作用。前期发现，一类β-arrestins偏好性的AT1R配体改善小鼠肾脏缺血再灌注损伤，降低体外肾小管上皮细胞损伤，其作用优于ARBs氯沙坦。在此基础上，本项目拟采用偏好性的AT1R配体，利用野生型小鼠、AT1R-/-小鼠、β-arrestin-1-/-小鼠、β-arrestin-2-/-小鼠造成缺血性急性肾损伤模型及AT1R过表达的肾小管上皮细胞缺氧-复氧损伤模型，确定β-arrestins通路偏好性的AT1R配体在缺血性急性肾损伤中的作用及其机制，为应用偏好性的AT1R配体防治缺血性急性肾损伤奠定基础。

The incidence of acute kidney injury is high and the prognosis is poor. Currently, there are few drugs available for acute kidney injury. Angiotensin Ⅱ receptor 1 (AT1R) blockers (ARBs) can improve acute renal injury, but it also increases the risk of renal injury. The project intends to screen a class of AT1R ligands that can retain the benefits of ARBs while reducing or removing its side effects. Recently, our experimental results indicated that β-arrestins biased AT1R ligand improved renal ischemia reperfusion injury in mice and protected against hypoxia-reoxygenation injury in renal tubular epithelial cells with AT1R overexpression. It showed that the action of β-arrestins biased AT1R ligand is better than ARBs losartan. To investigate the effect and mechanism of G protein / β-arrestins biased AT1R activation in ischemic acute kidney injury, biased AT1R ligands and AT1R blockers will be administrated to C57 mice, AT1R knockout mice, β-arrestin-1 knockout mice or β-arrestin-2 knockout mice with renal ischemia reperfusion injury, or renal tubular epithelial cells with hypoxia-reoxygenation. The data will provide foundation for the application of AT1R biased ligand in the prevention and treatment of ischemia acute kidney injury.