Role of the soluble (pro)renin receptor in blood pressure regulation

可溶性肾素（原）受体在血压调节中的作用

• 批准号: 10298453
• 负责人: NIRUPAMA RAMKUMAR
• 金额: $ 40.77万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-25 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10298453
• 关键词: Address; Aldosterone; Angiotensins; Attenuated; Biological; Blood Pressure; Blood Vessels; CRISPR/Cas technology; Cardiac; Cell membrane; Cell physiology; Cells; Cleaved cell; DOCA; Defect; Development; Equilibrium; Excretory function; Future; Goals; Heart Injuries; Heart failure; Hypertension; Inactive Renin; Infusion procedures; Injury to Kidney; Intake; Kidney; Kidney Diseases; Lead; Length; Maintenance; Measures; Mediating; Mesenteric Arteries; Molecular; Morbidity - disease rate; Mus; Mutagenesis; Mutant Strains Mice; Nitric Oxide; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmacology; Physiological; Plasma; Play; Polyuria; Prostaglandin-Endoperoxide Synthase; Recombinants; Regulation; Renin; Renin-Angiotensin System; Role; Signal Pathway; Signal Transduction; Site; Sodium Chloride; System; Tissues; Tubular formation; Vasodilation; Water; base; blood pressure reduction; blood pressure regulation; epithelial Na+ channel; heart function; inhibitor/antagonist; innovation; male; mortality; mouse model; mutant; novel; novel therapeutic intervention; organ injury; patch clamp; receptor; receptor function; response; salt sensitive hypertension; urinary; vasoconstriction

Abstract The renin angiotensin system (RAS) plays a vital role in the maintenance of blood pressure (BP). The (pro)renin receptor (PRR) is a recently discovered component of the RAS, implicated in the pathogenesis of hypertension. The PRR can exist as the full length form, bound to cell membrane or be cleaved to generate a soluble PRR (sPRR) and M8.9 fragments. Although the function of the full-length PRR both at a molecular and system level is being unraveled, the biologic role of sPRR remains largely unknown. Hence, we developed a novel mouse model with absence of sPRR using CRISPR-Cas9 directed mutagenesis of the PRR cleavage site. The following specific aims will be addressed: 1. Investigate the physiological role and mechanisms involved in sPRR regulation of BP. BP will be examined in control and mutant mice lacking sPRR on normal, low and high Na+ intake focusing on renal, cardiac and vascular function. The contribution of nitric oxide and cyclooxygenase signaling pathways in sPRR regulation of blood pressure will be determined. 2. Investigate the pathophysiological role of sPRR in hypertension. Control and mutant mice lacking sPRR will be studied under Ang-II dependent (Ang-II infused) or Ang-II independent (DOCA-salt) hypertensive conditions. This proposal will establish the role of sPRR in BP regulation under physiological conditions and pathogenic role in hypertension. The integrative approach used herein will identify global and tissue-specific effects of sPRR and may help in the development of a new therapeutic approach for hypertension targeting the sPRR. These studies are in line with our long-term goal of defining the role of RAS components, particularly prorenin and the PRR, in hypertension and associated complications.

摘要 肾素血管紧张素系统（RAS）在维持血压中起着重要作用 （英国石油公司）。（原）肾素受体（PRR）是最近发现的RAS的组成部分， 高血压的发病机制。PRR可以以全长形式存在，与细胞结合 膜或被切割以产生可溶性PRR（sPRR）和M8.9片段。虽然 全长PRR在分子和系统水平上的功能正在解开， sPRR的生物学作用仍然在很大程度上未知。因此，我们开发了一种新的小鼠模型， 使用PRR切割位点的CRISPR-Cas9定向诱变来检测sPRR的不存在。的 将实现以下具体目标： 1.研究sPRR调节BP的生理作用和机制。BP 将在正常、低和高Na+摄入的缺乏sPRR的对照和突变小鼠中进行检查 专注于肾脏、心脏和血管功能。一氧化氮的贡献， 将确定sPRR调节血压中的环氧合酶信号传导途径。 2.探讨sPRR在高血压中的病理生理作用。对照和突变小鼠 缺乏sPRR的患者将在Ang-II依赖性（Ang-II输注）或Ang-II非依赖性下进行研究 （DOCA-盐）高血压病症。 这一提议将确立生理条件下sPRR在BP调节中的作用 和高血压的致病作用。本文采用的综合方法将确定全球和 sPRR的组织特异性作用，可能有助于开发新的治疗方法 针对sPRR的高血压治疗。这些研究符合我们的长期目标， RAS组分，特别是前肾素和PRR，在高血压及相关疾病中的作用 并发症