Prostaglandins activation of erythropoietin production and erythroid progenitor cells.

A model is presented postulating a role for prostaglandins E and prostacyclin in kidney generation of erythropoietin and the activation of the erythroid progenitor cell (CFU-E) compartment by erythropoietin (Ep). Several criteria have been met to prove that prostanoids mediate erythropoiesis: 1) several E-type prostaglandins (PGE2, 15-methyl prostaglandin E2, 16,16-dimethyl E2, 6-keto-E1 and PGE1) produced a significant increase in radioiron incorporation in red cells of exhypoxic polycythemic mice; 2) prostaglandin E2 increased kidney production of erythropoietin in the isolated perfused dog kidney; 3) arachidonic acid, a precursor for all bisenoic prostaglandins, increased kidney production of erythropoietin in the isolated perfused dog kidney which was blocked by pretreatment with the cyclo-oxygenase inhibitor drug indomethacin; 4) hypoxemic perfusion of the isolated perfused dog kidney increased kidney production of erythropoietin and produced an elevation in prostacyclin in the perfusates; 5) albuterol, a beta-2 adrenergic agonist, produced a significant increase in perfusate levels of erythropoietin and PGE in the isolated perfused dog kidney; 6) renal ischemia increased Ep and PGE levels in renal venous plasma which was blocked by pretreatment with indomethacin; 7) prostaglandin E2 and arachidonic acid produced a significant increase in erythroid colonies (CFU-E) in vitro in normal mouse bone marrow; 8) E-type prostaglandins (15-methyl E2) increased in vivo erythroid colony (CFU-E) formation in bone marrows of post-hypoxic polycythemic mice; and 9) injections of 15-methyl E2 daily for six weeks in normal and hypoxic mice produced a significant elevation in the total circulating red cell mass. These studies indicate that hypoxic stimulation of kidney production of erythropoietin may be related to the generation of prostacyclin (PGI2). On the other hand, albuterol and ischemic (reduction in renal blood flow) stimulation of kidney production of erythropoietin involves prostaglandins of the E type. In addition, E-type prostaglandins were found to enhance the effects of erythropoietin in activating erythroid progenitor cells (CFU-E) in the bone marrow. We postulate from our model that prostaglandins E and prostacyclins are involved in the mechanism of kidney production of erythropoietin as well as the activation of the Ep-responsive cell (ERC) compartment.