(Pro)rennin receptor (PRR) is a newly identified component of the renin-agiotensin system, being capable of binding to renin and its inactive precursor prorenin to activate renin and also triggering intracellular signaling involving ERK (extracellular-signal-regulated kinase) ½. Abundant expression of PRR was demonstrated in the collecting duct where it was stimulated by angiotensin II, which may serve as a positive feedback loop to amplify the local action of the RAS in the renal medulla. However, the mechanism of Ang II induced PRR expression in the collecting duct (CD) remains unknown. The goal here was to test whether cycloxygenase-2 (COX-2), an important regulator of renal medullary function, was involved in this phenomenon. Exposure of primary rat inner medullary collecting duct (IMCD) cells for 12 hours induced a parallel induction of PRR protein (mRNA: 1.10 ± 0.37; P=NS; protein: 1.43±0.08 fold change; P<0.05) and COX-2 mRNA and protein (mRNA: 1.34±0.15; P<0.05; protein: 1.34 ± 0.17 fold change; P<0.05), as assessed by immunoblotting and qRT-PCR. When the cells were pretreated with a specific COX-2 inhibitor NS-398, Ang II-induced upregulation of PRR protein expression was almost completely abolished. Treatment with exogenous PGE2 at 1 μM for 12 hours induced an 2.6-fold increase in PRR protein expression and also completely reversed inhibitory effect of NS-398 on Ang II-induced stimulation of PRR expression. To assess which EP receptor was involved in the PRR upregulation, we used specific EP receptor antagonists: SC-51382 (for EP1; 10 nmol/L), L-798106 (for EP3; 10 μmol/L) and L-161982 (for EP4; 10 μmol/L). The upregulation of PRR expression by Ang II was nearly abolished by L-161982, and partially suppressed by SC-51382, but was unaffected by L-798106. On the contrary, the COX-2 stimulation by Ang II was enhanced by L-161982, but was unaffected by SC-51382 or L-798106. We conclude that: 1) Ang II stimulates CD PRR expression via COX-2-derived PGE2 acting through EP4 and EP1 receptors, and 2) a negative feedback loop involving EP4-mediated inhibition of COX-2 expression exists to mitigate the exaggerated PRR response to Ang II in the distal nephron.