The important role of renin-angiotensin-aldosterone system in the pathogenesis of hypertension is highlighted by the wide use of its inhibitors for treatment of hypertension. The current proposal will address the role of renal site-1 protease/soluble (pro)renin receptor in pathogenesis of salt-sensitive hypertension. The proposal has the potential to advance our understanding of the fundamental mechanism of hypertension and also to identify a novel target for antihypertensive therapies.
(Pro)renin receptor (PRR) is a new member of the renin-angiotensin system (RAS) and has emerged as a key regulator of renal handling of Na+ and water balance, blood pressure (BP), and the intrarenal RAS. Protease- mediated cleavage of PRR generates soluble PRR (sPRR), the extracellular domain of this protein. Circulating sPRR is widely regarded as a biomarker for a number of human diseases such as cardiovascular disease, chronic kidney disease, etc. Recently, we first reports a novel biological function of sPRR in regulation of fluid balance. While furin and ADAM19 were originally thought to mediate sPRR production, new evidence demonstrated site-1 protease (S1P) as the predominant cleavage enzyme. Therefore, the goal of this proposal is to define the regulation and function of S1P- derived sPRR in renal handling of Na+ balance and BP. Compelling preliminary data demonstrated that S1P is indispensable to Aldo-induced ENaC activation and is also implicated in the development of salt- sensitive hypertension in Dahl S (SS) rats via generation of sPRR. It is further intriguing that sPRR directly interacts and activates angiotensin type 1 receptor (AT1R) to induce ?-ENaC expression. Therefore, we hypothesize that S1P-derived sPRR induced ENaC activation via interaction with AT1R, thus serving a common downstream pathway responsible for salt-sensitive hypertension. To test this hypothesis, we will define the function of S1P/sPRR in different salt-sensitive hypertensive models with use of pharmacological inhibitors or renal tubule-wide deletion of S1P. Reversibility of the effect of S1P inhibition is tested by supplement of exogenous sPRR. Lastly, we propose to test the direct interaction between sPRR and AT1R and further explore its implication in regulation of ENaC. Overall, this proposal is expected to offer novel insight into the function of a newly described S1P/sPRR pathway in the kidney.
