Endothelial sphingosine-1-phosphate receptor 1 regulates renal recovery after acute kidney injury

 描述(由申请人提供)：急性肾损伤(AKI)后进展为纤维化可能是不适应修复过程的结果，并可加重肾功能障碍。血管内皮细胞是血管内稳态的基础，AKI后血管功能不全可能导致组织缺血、肾小管间质损伤和激活、进行性纤维化的恶性循环。鞘氨醇1-磷酸1受体(S1P1)是一种G蛋白偶联受体，负责维持内皮屏障的完整性和功能。本项目的目的是确定I-S1P1对于内皮功能和预防纤维化的AKI的恢复是必要的。在具体目标1中，我们的初步工作是使用Cre-loxP系统诱导AKI后内皮细胞S1P1的缺失，证明S1P1是恢复肾功能和预防早期纤维化所必需的。我们建议明确界定血管内皮细胞S1P1在AKI后血管功能恢复中的作用。在特定的目标2中，我们认为S1P1保护肾内皮细胞的功能，并防止周细胞的促纤维化反应。我们将在体外操纵S1P1在内皮细胞中的表达，以确定其对内皮细胞的保护作用及其与周细胞相互作用的细胞机制。本研究的意义在于，它将为在急性肾损伤后恢复的关键时期使用内皮细胞S1P1的药理激活作为一种新的治疗策略以保护内皮功能以防止纤维化提供基础。

 DESCRIPTION (provided by applicant): Progression to fibrosis after acute kidney injury (AKI) may result from maladaptive repair processes and can potentiate kidney dysfunction. The endothelium is the keystone of vascular homeostasis, and vascular insufficiency after AKI may result in a vicious cycle of tissue ischemia, tubulointerstitial damage and activation, and progressive fibrosis. Sphingosine 1-phosphate 1 receptor (S1P1), a G-protein coupled receptor, maintains endothelial barrier integrity and function. The purpose of this project is to determine i S1P1 is necessary for endothelial function and recovery from AKI in prevention of fibrosis. In Specific Aim 1, our preliminary work using a Cre-loxP system to induce deletion of S1P1 in endothelial cells after AKI demonstrates that S1P1 is necessary for recovery of kidney function and prevents early onset fibrosis. We propose to clearly define the contribution of S1P1 in endothelial cells to recovery of vascular function after AKI. In Specific Aim 2, we propose that S1P1 protects kidney endothelial function and prevents a pro-fibrotic response by pericytes. We will manipulate S1P1 expression in endothelial cells in vitro to determine cellular mechanisms underlying its protective role in endothelial cells and their interaction with pericytes. The significance of this research is that it will provide the basis for using pharmacological activatio of endothelial S1P1 as a novel therapeutic strategy for preserving endothelial function during a critical period of recovery after AKI to prevent fibrosis.