Abstract 098: Collecting Duct-derived (pro)renin Receptor Contributes To 2-kidney, 1-clip-induced Renovascular Hypertension And Ischemic Nephropathy In Mice

Abstract

The 2-kidney, 1-clip (2K1C) Goldblatt model features overactivation of the systemic renin-angiotensin-aldosterone system (RAAS) due to increased renin release from juxtaglomerular cells. However, no prior study functionally evaluates possible involvement of the intrarenal RAAS in this model. Within the kidney, (pro)renin receptor (PRR) is predominantly expressed in the collecting duct (CD) implicated in regulation of the intrarenal RAAS under physio-pathological conditions. In the present study, we employed a mouse model of CD-specific deletion of PRR (CD PRR KO) to examine the role of CD PRR in pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy and to further explore the underlying mechanism. Floxed and CD PRR KO mice were subjected to sham-operation or 2K1C procedure, followed by analysis of blood pressure, renal injury, and indices of the RAAS, as well as the expression of subunits of ENaC. Clipping-induced hypertension and renal injury were both attenuated in CD PRR KO mice as compared with floxed controls (MAP on day24: Floxed/2K1C 148.2±3.9 mm Hg vs. CD PRR KO/2K1C 136.9±2.5 mm Hg, n=6, p < 0.05) (urinary albumin/creatinine: Floxed/2K1C 67.5±6.4 mg/g vs. CD PRR KO/2K1C 30.9±3.5 mg/g, n=6, p < 0.01). Of note, the reductions of clipping-induced protein abundance of fibronectin and α-SMA in CD PRR KO mice were 70% and 55%, respectively. Similarly, clipping induced paralleled increases in renal mRNA expression of IL-1β, TNF-α, MCP-1 and TGF-β1 in floxed mice, which were all blunted in CD PRR KO mice. The protective phenotype of the null mice was paralleled with suppressed intrarenal renin and aldosterone (Aldo) levels. In contrast, clipping-induced enhancement of circulating renin and Aldo remained unchanged between the genotypes. Moreover, renal medullary α-ENaC mRNA and protein expression was elevated by clipping in floxed mice, which was respectively blunted 52% and 54% in CD PRR KO mice. Together, these results suggest that the activation of CD PRR stimulates components of the intrarenal RAAS and renal medullary α-ENaC, which result in increased tubular sodium reabsorption and thus contribute to 2K1C-induced renovascular hypertension and ischemic nephropathy.