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Endothelial Epoxygenase, Kidney Injury, and Blood Pressure Regulation

内皮环氧合酶、肾脏损伤和血压调节

基本信息

批准号：
10415003
负责人：
John D Imig
金额：
$ 17.59万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2022-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415003
关键词：
Acids Acute Acute Renal Failure with Renal Papillary Necrosis Arachidonic Acids Attenuated Bilateral Blood Vessels Blood flow CYP2C19 gene Cell Adhesion Molecules Cell Culture Techniques Cell physiology Chronic Chronic Kidney Failure Cytochrome P450 Data Development Dilator Endothelial Cells Endothelium Epoxide hydrolase Functional disorder Glomerular Filtration Rate Goals Hydrolysis Hypertension Impairment Inflammation Injury Injury to Kidney Ischemia Kidney Kidney Calculi Kidney Diseases Lead Microcirculation Modeling Outcome Outcome Study Patients Pharmacology Recovery Regenerative capacity Renal Blood Flow Reperfusion Injury Reperfusion Therapy Rodent Model Testing Therapeutic Tissues Tubular formation Ureteral obstruction Vasodilation analog blood pressure reduction blood pressure regulation density design endothelial dysfunction epidemiology study genetic manipulation glomerular filtration hemodynamics hypertensive improved inhibitor ischemic injury novel novel therapeutics prevent protective effect renal artery renal ischemia repaired response restoration salt sensitive salt sensitive hypertension urinary tract obstruction

项目摘要

Epidemiological and outcomes studies in patients, as well as studies in rodent models, reveal that renal ischemic kidney injury and unilateral obstructive uropathy brings on long-term consequences: hypertension and chronic kidney disease. Major pathophysiological contributors include impaired renal hemodynamics, endothelial dilator dysfunction, and endothelial cell inflammation. Because the renal microcirculation lacks efficient regenerative capacity, acute damage to the microcirculation can lead to long-term changes in renal hemodynamics that predispose patients to hypertension and chronic kidney disease. A class of arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs) increase renal blood flow and improve endothelial cell function. Not known is the contribution of CYP2C epoxygenases, soluble epoxide hydrolase (sEH), and regioisomeric EETs to salt-sensitive hypertension and chronic kidney disease following obstructive uropathy and renal ischemic injury. We hypothesize that decreased endothelial EET levels result in endothelial dysfunction and impaired renal hemodynamics following renal ischemic injury or urinary tract obstruction. The immediate goals of this project are to determine the ability for endothelial EETs to improve endothelial- dependent afferent arteriolar dilation, to decrease endothelial inflammation, and to prevent salt-sensitive hypertension and chronic kidney disease following unilateral ureter obstruction (UUO) or ischemia/reperfusion (I/R) kidney injury. This project will utilize pharmacological as well as global and tissue-specific genetic manipulation of CYP2C, sEH, and EETs. We will obtain our immediate goals by completing three aims. Aim 1 will test the hypothesis that decreased EET levels or EET function contributes to the development of salt- sensitive hypertension and chronic kidney disease following UUO or I/R kidney injury. Aim 2 will test the hypothesis that increasing endothelial EET levels will improve renal microvascular endothelial function following UUO or I/R kidney injury to prevent salt-sensitive hypertension and chronic kidney disease. Aim 3 will test the hypothesis that pharmacological approaches to increase EET levels can prevent the long-term salt-sensitive hypertensive and chronic kidney injury following UUO or I/R kidney injury. Accordingly, our findings promise to advance the field forward by not only enhancing our understanding of the pathophysiological mechanisms whereby UUO or I/R kidney injury leads to chronic kidney disease but also leading to new therapeutic treatments.

患者的流行病学和结局研究，以及啮齿动物模型的研究表明，肾缺血