Role of prostaglandins in hypoxia-stimulated erythropoietin production

The role of prostaglandins in the mediation of hypoxia-stimulated erythropoietin (Ep) production by cultured rat renal mesangial cells was examined. It was found that an increase in prostaglandin E₂ (PGE₂) production accompanied the rise in Ep due to hypoxia (2% O₂). The hypoxia-stimulated increase in Ep production was abolished in the presence of the cyclooxygenase inhibitor indomethacin (10^-5 M). When PGE₂ (10^-6 M) was added simultaneously with indomethacin, however, no diminution in hypoxia-stimulated Ep production was observed. Addition of arachidonic acid (AA, 10^-5 M), PGE₂ (10^-6 M), or PGI₂ (10^-4 M) enhanced Ep production under normoxic conditions (20% O₂), while PGF(2α) (10^-6 M) had no effect on Ep production. AA, PGE₂, and PGI₂ were found to stimulate adenosine 3',5'-cyclic monphosphate formation by the cultured mesangial cells. Enhancement of adenylate cyclase activity by forskolin (10^-5 M) also increased Ep production in the cell cultures. Our results suggest that hypoxia-stimulated Ep production by cultured mesangial cells is mediated by prostaglandins with subsequent stimulation of adenylate cyclase activity.