The Prostaglandin EP4 Receptor Mediates Angiotensin II-Induced (Pro)Renin Receptor Expression in the Rat Renal Medulla

AngII stimulates (pro)renin receptor (PRR) expression in the renal collecting duct (CD), triggering the local renin response in the distal nephron. Our recent study provided evidence for involvement of COX-2-PGE2 pathway in AngII-dependent stimulation of PRR expression in the CD. Here we tested the role of EP subtypes acting downstream of COX-2 in this phenomenon. In primary rat inner medullary collecting duct (IMCD) cells, AngII treatment for 12 h induced a 1.8-fold increase in the full-length PRR protein expression. To assess the contribution of EP receptor, the cell were pre-treated with specific EP receptor antagonists: SC-51382 (for EP1), L-798106 (for EP3), and L-161982 (for EP4) and ONO-AE3-208 (ONO, a structurally distinct EP4 antagonist). The upregulation of PRR expression by Ang II was consistently abolished by L-161982 and ONO, and partially suppressed by SC-51382, but was unaffected by L-798106. The PRR expression was also significantly elevated by the EP4 agonist CAY10598 in the absence of AngII. Sprague-Daley rats were subsequently infused for 1 or 2 weeks with vehicle, AngII alone or in combination with ONO. AngII infusion induced parallel increases in renal medullary PRR protein, and renal medullary and urinary renin activity and total renin content, all of which were blunted by ONO. Both tail cuff plethysmography and telemetry demonstrated attenuation of AngII hypertension by ONO. Overall, these results have established a crucial role of the EP4 receptor in mediating the upregulation of renal medullary PRR expression and renin activity during AngII hypertension.