(Pro)renin receptor (PRR) is abundantly expressed in the collecting duct (CD) and the expression is further induced by angiotensin II (AngII). The present study was conducted to investigate the role of CD PRR during AngII-induced hypertension and to further explore the underlying mechanism. Radiotelemetry demonstrated that a 1-wk AngII infusion gradually and significantly induced hypertensive response in floxed mice and this response was significantly attenuated in mice lacking PRR in the CD (termed CD PRR KO). AngII infusion in floxed mice increased urinary renin activity and selectively induced renal medullary α-ENaC mRNA and protein expression, all of which were blunted in the null mice. In cultured mpkCCD cells grown in Transwells, transepithelial Na+ transport as measured by using volt-ohmmeter was transiently stimulated by acute AngII treatment, which was abolished by a PRR antagonist PRO20. In a chronic setting, AngII treatment induced α-ENaC mRNA expression in mpkCCD cells, which was similarly blocked by PRO20. Chronic intramedullary infusion of an ENaC inhibitor amiloride in rats significantly attenuated AngII-induced hypertension. Overall, the present study suggests that CD PRR contributes to AngII-induced hypertension at least partially via activation of renal medullary ENaC.