Prostaglandin E2 stimulates cystogenesis through EP4 receptor in IMCD-3 cells

Previously, we demonstrated that prostaglandin E2 (PGE2) induced cAMP and cyst formation through PGE2 receptor-2 (EP2) activity in human autosomal-dominant polycystic kidney disease (ADPKD) epithelial cells. In this study, we determined the role of EP2 and EP4 receptors in mediating PGE2 stimulation of cAMP signaling and cystogenesis in mouse renal epithelial cells using the inner medullary collecting duct-3 (IMCD-3) cell line. In contrast to human ADPKD cells, using novel EP2 and EP4 antagonists, we found that IMCD-3 cells expressed functional EP4 but not EP2, which stimulated cAMP formation and led to cyst formation in 3D culture system. The involvement of EP4 receptors in IMCD-3 cells was further supported by the specific effect of EP4 siRNA that inhibited PGE2-induced cystogenesis. We also observed different cellular localization of EP2 or EP4 receptors in IMCD-3 transfected cells. Collectively, our results suggest an important role of different expression of EP2 or EP4 receptors in the regulation of cystogenesis.

► EP4 and not EP2 receptor mediates cAMP stimulation by PGE2 in mouse IMCD-3 cell line. ► CJ-42794, an EP4 receptor antagonist, blocks PGE2 effect in IMCD-3 cell cultures. ► PGE2-stimulated cystogenesis involves EP2 or EP4 receptors dependently on cell types. ► EP2 and EP4 receptors display different localization in transfected IMCD-3 cells.