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

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 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.