Abstract P236: Site-1 Protease-derived Soluble (Pro) Renin Receptor Mediates Angiotensin II-induced Hypertension via Activation of Intrarenal Renin System

Abstract

We have previously shown that collecting duct (CD)-specific deletion of (pro)renin receptor (PRR) attenuates angiotensin II (Ang II)-induced hypertension, accompanied with reduced soluble PRR (sPRR) that exerts antidiuretic action. Recent preliminary and published results demonstrated site-1portease (S1P) but not furin or ADMA19 as the predominant PPR cleavage enzyme. In the present study, we evaluated involvement of S1P-derived sPRR in Ang II-induced hypertension. By radiotelemetry, CD PRR KO mice exhibited reduced MAP on day 7 of Ang II infusion at 300 ng/kg/min as compared with floxed mice (MAP: 118±5 vs. 137±3 mmHg, N=5, p<0.05). Administration of sPRR-His, a histidine-tagged sPRR, at 120 μg/kg/d via i.v. infusion to CD PRR KO mice for additional 7 days largely restored the sensitivity to Ang II (MAP: 139±6 mmHg in sPRR-His +Ang II group vs. 116±5 mmHg in Ang II group, N = 4, p<0.05). The i.v. infusion was achieved via placement of a catheter in jugular vein with the other end connected to mimipump. In C57/BL6 mice, administration of a S1P inhibitor PF429242 (PF) via mini pump infusion at 30 mg/kg/d for 7 days attenuated Ang II-induced increases in MAP (day 7: 125±5 in Ang II+ PF group vs. 142±3 in Ang II group; N=6, p<0.05), urinary sPRR excretion (27±4 vs. 63±9 pg/24h; N=6, p<0.05). In parallel, urinary renin levels were elevated by Ang II, which was blunted by PF (renin activity: 0.17±0.03 in Ang II+PF vs. 0.80±0.081 in Ang II vs. 0.12±0.016 ng/24h in Control, N=6, p<0.01; active renin content: 15.2±2.7 vs. 236.0±23.2 vs. 5.6±1.3 ng/24h, N=6, p<0.01; prorenin content: 9.6±3.1 vs. 27.8±6.1 vs. 6.2±1.8 ng/24h, N=6, p<0.05; total renin content: 24.8±5.2 vs. 263.8±27.0 vs. 11.8±3.0 ng/24h, N=6, p<0.01). An intravenous infusion of sPRR-His counteracted the blood pressure-lowering effect of PF in Ang II-infused mice (MAP: 147±3 in PF+sPRR vs. 126±4 mmHg in PF; N=4, p<0.05). Together, these results suggest that S1P-derived sPRR contributes to Ang II-induced hypertension through activation of intrarenal renin-angiotensin system.