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

摘要 肾素血管紧张素系统(RAS)在维持血压方面起着至关重要的作用 (BP)。(Pro)肾素受体(PRR)是最近发现的RAS的一个成分，与 在高血压的发病机制中起重要作用。PRR可以作为与细胞结合的全长形式存在 膜或被切割产生可溶性PRR(SPRR)和M8.9片段。尽管 全长PRR在分子和系统水平上的功能正在被揭开， SPRR的生物学作用在很大程度上仍不清楚。因此，我们开发了一种新的小鼠模型 使用CRISPR-Cas9直接突变PRR裂解位点而不存在sPRR。这个 将解决以下具体目标： 1.探讨sPRR调节血压的生理作用及机制。BP 将在正常、低钠和高钠摄入量下检测缺乏sPRR的对照和突变小鼠 专注于肾脏、心脏和血管功能。一氧化氮的贡献和 环氧合酶在sPRR调节血压中的信号通路将被确定。 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的研究将在Ang-II依赖(Ang-II输注)或Ang-II非依赖下进行 (DOCA-SALT)高血压条件。 这项建议将确立sPRR在生理条件下调节血压的作用。 以及在高血压中的致病作用。这里使用的综合方法将确定全球和 SPRR的组织特异性效应，可能有助于开发一种新的治疗方法 用于以sPRR为靶点的高血压。这些研究符合我们的长期目标，即确定 RAS组分，特别是Prorenin和PRR在高血压和相关疾病中的作用 并发症。

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.