A decade ago, (pro)renin receptor (PRR) was cloned as a new component of the renin-angiotensin system (RAS) with the capability to bind prorenin and renin to increase their catalytic activity. Soluble PRR (sPRR) is derived from the extracellular domain after cleavage by furin or ADMA19. Within the kidney, PRR is predominantly expressed in the collecting duct (CD) where its expression is elevated by AngII. Preliminary studies employing a novel PRR decoy peptide PRO20 demonstrated that intramedullary antagonism of PRR in rats produced remarkable attenuation of AngII-induced hypertension, renal medullary ?-ENaC expression, and kidney injury, in parallel with suppressed renal medullary renin response and urinary aldosterone excretion. Strikingly, after adrenalectomy, this treatment suppressed urinary aldosterone excretion to undetectable level in AngII-infused rats, indicating a dominant role of PRR in nonadrenal aldosterone synthesis in the kidney. In vitro studies provide strong evidence for a direct action of PRR/sPRR in regulation of ENaC activity and aldosterone release from cultured CD cells. Based on these results, we hypothesize that during AngII infusion, PRR expression is increased in the CD where it triggers the local renin/aldosterone response, leading to ENaC activation and hence hypertension. To define the functional role of PRR in the CD, we propose to produce CD-specific deletion of PRR and study its impact on AngII-induced hypertension, target organ damage, local renin/aldosterone response, and ENaC activation in vivo and in vitro. We employ intramedullary infusion and conditional gene targeting techniques to evaluate the contribution of CD ENaC to AngII-induced hypertension. Lastly, we will evaluate urinary sPRR as a biomarker and further study the functional role and mechanism of sPRR in regulation of CD Na+ transport and blood pressure. The current proposal is expected to offer new insight into the role of CD PRR in the pathogenesis of hypertension and kidney injury.
The important role of the renin-angiotensin system in the pathogenesis of hypertension is highlighted by the wide use of ACE or AT1 blockers for treatment of hypertension but the mechanism of how this system affects blood pressure or kidney injury is still incompletely understood. This proposal will contribute to defining the pathogenic role of (pro) renin receptor, a new member of the renin- angiotensin system, in pathogenesis of hypertension and kidney disease. This proposal is of high relevance to veteran's health in light of a large patient population suffering from these conditions.