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

摘要

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.