Abstract P221: Soluble (pro)renin Receptor Contributes To 2-kidney, 1-clip-induced Renovascular Hypertension And Ischemic Nephropathy In Mice

The Goldblatt two-kidney, one-clip (2K1C) model features renovascular hypertension and ischemic nephropathy due to overactivated renin-angiotensin system (RAS). Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease (S1P) and implicated as a potential regulator of the RAS and renal function. Here, we examined the function and underlying mechanism of sPRR in 2K1C model by pharmacological inhibition of S1P and genetic mutagenesis of S1P cleavage site. Male 2-mo-old C57BL/6 mice were subjected to the 2K1C procedure or sham operation for 1 month, followed by a 14-day infusion of vehicle or a specific S1P inhibitor PF429242 (PF) (30 mg/kg/day via minipump). The 2K1C procedure induced a 2-fold increase in plasma sPRR, which was reduced by 50% following PF treatment. This was paralleled by improvement of renovascular hypertension (MAP:142.1±1.3 vs. 129.9±2.8mmHg, n=7, p < 0.05) and cardiac hypertrophy (HW/BW:6.3±0.3 vs. 5.0 ± 0.3mg/g, n=7, p < 0.01) accompanied with suppressed cortical and medullary renin activity, active renin content, prorenin content and total renin content in clipped kidney. Meanwhile, cortical and medullary renin mRNA level in clipped kidney was increased 3.8-fold and 5.3-fold, which was reduced by 41% and 55% respectively, following PF treatment. The level of urinary albumin, KIM-1 and NGAL was elevated 5.1-fold, 4.0-fold and 5.7-fold after 2K1C surgery, which was blunted 35%, 49% and 59%, respectively, following PF treatment. Secondly, we employed a novel mouse model with mutagenesis of the cleavage site in PRR (termed as Mutant mice) to verify the role of endogenous sPRR in 2K1C model. Similarly, the hypertensive response and ischemic nephropathy of Mutant mice to 2K1C procedure was blunted (24-day MAP: 2K1C/WT 142.5±2.1 vs. 2K1C/Mutant 128.2±3.2mmHg; 24-day urinary albumin/creatinine: 2K1C/WT 64.9±7.2 vs. 2K1C/Mutant 33.0±1.9mg/g, n=6, p < 0.05), in parallel with attenuated response of systemic and intrarenal RAS. Together, consistent results with the different approaches have established an important role of S1P-derived sPRR in regulation of the RAS and thus the pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy.