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

内皮鞘氨醇-1-磷酸受体1调节急性肾损伤后的肾功能恢复

• 批准号: 9170932
• 负责人: Heather M. Perry
• 金额: $ 5.88万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9170932
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Affect; Attenuated; Blood Vessels; Blood flow; Cell Adhesion Molecules; Cell Survival; Cell physiology; Chronic; Coculture Techniques; Conditioned Culture Media; Culture Techniques; Data; Development; Effector Cell; End stage renal failure; Endothelial Cells; Endothelium; Epithelial; Fibroblasts; Fibrosis; Functional disorder; G-Protein-Coupled Receptors; Genetic; Homeostasis; Hypoxia; In Vitro; Inflammation; Inflammatory; Injury; Ischemia; Kidney; Kidney Diseases; Kidney Failure; Knock-out; Lead; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Long-Term Effects; Lymphocyte; Lysophospholipids; Maintenance; Mediator of activation protein; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Patients; Pericytes; Phase; Prevention; Process; Quality of life; Receptor Signaling; Recovery; Recovery of Function; Renal Blood Flow; Renal function; Reperfusion Injury; Research; Role; Secondary Prevention; Signal Transduction; Sphingosine-1-Phosphate Receptor; Tamoxifen; Testing; Therapeutic; Tissues; Ultrasonography; Vascular Diseases; Work; base; cell growth; cell type; contrast enhanced; critical period; defined contribution; design; early onset; endothelial dysfunction; experience; functional decline; high risk; improved; in vivo; interstitial cell; macrophage; monocyte; mortality; neutrophil; novel therapeutic intervention; novel therapeutics; prevent; promoter; public health relevance; receptor; receptor expression; recombinase-mediated cassette exchange; repaired; response; sphingosine 1-phosphate; therapeutic target; trafficking; transdifferentiation

 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.

 描述（由申请方提供）：急性肾损伤（阿基）后进展为纤维化可能由适应不良的修复过程引起，并可能加重肾功能障碍。内皮是血管稳态的基石，阿基后的血管功能不全可能导致组织缺血、肾小管间质损伤和活化以及进行性纤维化的恶性循环。鞘氨醇1-磷酸1受体（S1 P1）是一种G蛋白偶联受体，维持内皮屏障的完整性和功能。本项目的目的是确定iS 1 P1对于内皮功能和预防纤维化中阿基的恢复是必要的。在具体目标1中，我们使用Cre-loxP系统诱导阿基后内皮细胞中S1 P1缺失的初步工作表明，S1 P1对于肾功能恢复和预防早期纤维化是必需的。我们建议明确定义内皮细胞中S1 P1对阿基后血管功能恢复的贡献。在具体目标2中，我们提出S1 P1保护肾内皮功能并防止周细胞的促纤维化反应。我们将在体外操纵内皮细胞中的S1 P1表达，以确定其在内皮细胞中的保护作用及其与周细胞相互作用的细胞机制。这项研究的意义在于，它将为使用内皮S1 P1的药理学激活作为在阿基后恢复的关键时期保护内皮功能以预防纤维化的新治疗策略提供基础。