A concept for the control of kidney production of erythropoietin involving prostaglandins and cyclic nucleotides.
Our hypothesis is that PGs released within the kidney play a role in the modulation of kidney production of Ep. PGs release probably at medullary and/or cortical sites following erythropoietic stimuli such as hypoxic hypoxia, anemic hypoxia, and ischemic hypoxia induced by renal artery constriction increase kidney production of Ep. PGs which are released probably activate a renal cortical adenylate cyclase thereby enhancing the production of intracellular cAMP. This initiates the cascade of events resulting in the production and/or secretion of Ep by the kidney. The endoperoxide analogs and PGE2 have been found to produce a dose-related and Ep-dependent increase in radioiron incorporation into newly formed red blood cells of exhypoxic polycythemic mice. Indomethacin, a potent PG cyclo-oxygenase inhibitior, attenuates Ep production and the appearance of PGE in the renal venous effluent of animals exposed to hypoxic hypoxia and renal artery constriction. Arachidonic acid (C20:4) and PGE2 infusion into the posthypoxic isolated perfused dog kidney produced a significant elevation in Ep titers in the perfusate. The increase in Ep production caused by arachidonate is blocked by indomethacin. It has been previously reported that PGs of the E series stimulate cAMP formation in several tissues. We have found that not only are renal cortical cAMP levels significantly elevated in rats following exposure to hypobaric hypoxia but that dibutyryl cAMP administration produces an increase in hematocrit and circulating red cell mass in normal mice. Our data thus far strongly support the hypothesis that the renal PGs and the cyclic nucleotides are intimately involved in the pharmacologic and/or pathophysiologic control of Ep production. Further work is necessary to determine whether the PGs and cyclic nucleotides are involved in the day-to-day control of Ep production by the mammalian kidney.
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D004285:Dogs; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000378:metabolism*; D000860:Hypoxia / Q000503:physiopathology; D007213:Indomethacin / Q000494:pharmacology; D007501:Iron / Q000097:blood; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D011453:Prostaglandins / Q000502:physiology*; D011458:Prostaglandins E / Q000494:pharmacology; D011460:Prostaglandins F / Q000494:pharmacology
D011453:Prostaglandins; D011458:Prostaglandins E; D011460:Prostaglandins F; D004921:Erythropoietin; D000242:Cyclic AMP; D007501:Iron; D007213:Indomethacin