(Pro)renin receptor (PRR) is predominantly expressed in the distal nephron where it is activated by angiotensin II (AngII), resulting in increased renin activity in the renal medulla thereby amplifying the de novo generation and action of local AngII. The goal of the present study was to test the role of cycloxygenase-2 (COX-2) in meditating AngII-induced PRR expression in the renal medulla in vitro and in vivo. Exposure of primary rat inner medullary collecting duct (IMCD) cells to AngII induced sequential increases in COX-2 and PRR protein expression. When the cells were pretreated with a COX-2 inhibitor NS-398, Ang II-induced upregulation of PRR protein expression was almost completely abolished, in parallel with the changes in medium active renin content. The inhibitory effect of NS-398 on the PRR expression was reversed by adding exogenous PGE2. A 14-day AngII infusion elevated renal medullary PRR expression and active and total renin content in parallel with increased urinary renin, all of which were remarkably suppressed by the COX-2 inhibitor celecoxib. In contrast, plasma and renal cortical active and total renin content were suppressed by AngII treatment, an effect that was unaffected by COX-2 inhibition. Systolic blood pressure (SBP) was elevated with AngII infusion, which was attenuated by the COX-2 inhibition. Overall, the results obtained from in vitro and in vivo studies have established a crucial role of COX-2 in mediating upregulation of renal medullary PRR expression and renin content during AngII hypertension.