Prostaglandin E₂ Induces Prorenin-Dependent Activation of (Pro)renin Receptor and Upregulation of Cyclooxygenase-2 in Collecting Duct Cells

Background Prostaglandin E2 (PGE₂) regulates renin expression in renal juxtaglomerular cells. PGE₂ acts through E-prostanoid (EP) receptors in the renal collecting duct (CD) to regulate sodium and water balance. CD cells express EP1 and EP4, which are linked to protein kinase C (PKC) and PKA downstream pathways, respectively. Previous studies showed that the presence of renin in the CD, and that of PKC and PKA pathways, activate its expression. The (pro)renin receptor (PRR) is also expressed in CD cells, and its activation enhances cyclooxygenase-2 (COX-2) through extracellular signal–regulated kinase (ERK). We hypothesized that PGE₂ stimulates prorenin and renin synthesis leading to subsequent activation of PRR and upregulation of COX-2. Methods We used a mouse M-1 CD cell line that expresses EP1, EP3 and EP4 but not EP2. Results PGE₂ (10⁻⁶ M) treatment increased prorenin and renin protein levels at 4 and 8 hours. No differences were found at 12-hour after PGE₂ treatment. Phospho-ERK was significantly augmented after 12 hours. COX-2 expression was decreased after 4 hours of PGE₂ treatment, but increased after 12 hours. Interestingly, the full-length form of the PRR was upregulated only at 12 hours. PGE₂-mediated phospho-ERK and COX-2 upregulation was suppressed by PRR silencing. Conclusions Our results suggest that PGE₂ induces biphasic regulation of COX-2 through renin-dependent PRR activation via EP1 and EP4 receptors. PRR-mediated increases in COX-2 expression may enhance PGE₂ synthesis in CD cells serving as a buffer mechanism in conditions of activated renin-angiotensin system.