Abstract Body: The 2-kidney, 1-clip (2K1C) Goldblatt model features increased renin release from juxtaglomerular (JG) cells and subsequent activation of the systemic renin-angiotensin system (RAS). Besides the JG cells, renin level is also elevated in the collecting duct (CD) with unclear functional implications. Here we employed a mouse model of CD-specific deletion of renin (CD renin KO) to examine the role of CD renin in pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy and to further explore the underlying mechanism. Male 3-4-mo-old CD renin KO mice and their floxed controls 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 attenuated in parallel in CD renin KO mice as compared with floxed controls (MAP on day 21: Floxed/2K1C 149.8±4.5 mm Hg vs. CD renin KO/2K1C 135.9±2.9 mm Hg, n=7, p < 0.05) (urinary albumin/creatinine: Floxed/2K1C 78.5±5.7 mg/g vs. CD renin KO/2K1C 37.5±3.5 mg/g, n=7, p < 0.01). The reductions of clipping-induced protein abundance of fibronectin and α-SMA in CD renin KO mice were 49% and 58%, 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 renin 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 expression was elevated by clipping in floxed mice, which was blunted by 48% in CD renin KO mice. Together, these results suggest that the activation of CD renin stimulates components of the intrarenal RAAS and renal medullary α-ENaC, contributing to 2K1C-induced hypertension as well as ischemic nephropathy.