Abstract P002: Soluble (pro)renin Receptor Contributes To Angiotensin II-Induced Hypertension In Mice

Abstract

Activation of (pro)renin receptor (PRR) contributes to enhancement of intrarenal RAS and renal medullary α-ENaC and thus elevated blood pressure during angiotensin II (AngII) infusion. Soluble PRR (sPRR), the extracellular domain of PRR, is generated by multiple proteases including furin or ADAM19, and recently site-1 protease (S1P). The goal of the present study was to test the role of S1P-derived sPRR mediated AngII-induced hypertension. F1 B6129SF1/J mice were infused for 6 days with control (CTR) or AngII at 300 ng/kg/day alone or in combination with S1P inhibitor PF-429242 (PF) and blood pressure was monitored by radiotelemetry. S1P inhibition significantly attenuated AngII-induced hypertension accompanied with suppressed urinary and renal medullary renin levels and expression of renal medullary but not renal cortical α-ENaC expression. The effects of S1P inhibition were all reversed by supplement with histadine-tagged sPRR termed as sPRR-His. Mutagenesis of overlapping recognition site for S1P and furin in PRR for was generated in mice by CRISPR strategy (termed as mutant mice). Mutant mice were fertile and developed normally with a 50% reduction plasma sPRR. These mice exhibited blunted hypertensive response to AngII infusion accompanied with suppressed intrarenal renin levels. Ussing chamber technique was performed to determine amiloride-sensitive short-circuit current, an index of ENaC activity in confluent mpkCCD cells exposed for 24 h to AngII, AngII + PF, or AngII + PF + sPRR-His. AngII-induced ENaC activity was blocked by PF, which was reversed by sPRR-His. Together, these results support that sPRR derived from S1P or in combination with furin mediates AngII-induced hypertension through enhancement of intrarenal renin level and activation of ENaC.