Loss of Soluble (Pro)renin Receptor Attenuates Angiotensin-II Induced Hypertension and Renal Injury

Abstract

Rationale: Cleavage of the extracellular domain of the PRR ([pro]renin receptor) yields a soluble fragment (sPRR). Although changes in plasma sPRR levels have been reported in hypertension, the causal role of sPRR in blood pressure regulation is unknown. Objective: Determine the role of sPRR in blood pressure regulation at baseline and following Ang II (angiotensin II)-induced hypertension. Methods and Results: CRISPR-Cas9 was used to mutate the cleavage site of the PRR such that sPRR is not generated. Because the gene encoding PRR is on the X-chromosome and male mutant sPRR mice are infertile, only male mice were studied. Mutant sPRR mice had virtually undetectable plasma sPRR levels compared with littermate controls. Mutant sPRR mice had normal survival and development and no apparent histological abnormalities in the kidney, heart, or aorta despite lower body weight. During normal Na+intake, no differences in food or water intake, urinary water or Na+excretion, or acid-base status were observed between control and mutant sPRR mice. Compared with controls, mutant sPRR mice had lower blood pressure at baseline and an attenuated hypertensive response to 2 weeks of Ang II infusion (400 ng/kg per minute) which was partially reversed by infusion of mouse recombinant sPRR. Mutant sPRR mice also had lower albuminuria, renal tubular injury, and oxidative stress relative to control mice post-Ang II infusion. Furthermore, mesenteric arteries from mutant sPRR mice displayed reduced Ang II-induced vasocontraction and greater acetylcholine, but not sodium nitroprusside, evoked vasorelaxation under baseline conditions. Conclusions: Loss of sPRR reduces blood pressure at baseline and decreases Ang II-induced hypertension and renal injury. These effects of sPRR loss are associated with greater endothelium-dependent but not independent vasorelaxation of resistance-sized arteries.