The primary objective of the current proposal continues to be to determine the mechanism by which hypoxia stimulates kidney production of erythropoietin and the possible involvement of prostaglandins, the beta-adrenergic nervous system and cyclic nucleotides in this process. We postulate that prostaglandins/prostacyclin released during hypoxia trigger adenylate cyclase in a renal cell to increase cyclic AMP levels which initiate a cascade of events leading to the production of erythropoietin. The work which will be undertaken during the next year will be: 1) to determine the role that adenylate cyclase activation by prostaglandin E2 and prostacyclin may play in kidney production erythropoietin as a possible mechanism by which hypoxia triggers kidney production of erythropoietin; 2) assess the role of hypoxemia on calcium entry into renal cells to activate phospholipase initiating the prostaglandins cascade leading to erythropoietin production; 3) to study the effects of several prostaglandins E and prostacyclin analogues in the mechanisms of erythropoietin induced erythroid progenitor cell (FU-E and BFU-E) activation; 4) to study further the involvement of prostaglandins and prostacyclins in beta-2 adrenergic activation of kidney production of erythropoietin; 5) characterize the PGE2 and beta-2 adrenergic-adenylate cyclase coupling in the induction of erythroleukemia cells (mouse spleen Friend virus) and bone marrow cells from patients with myeloproliferative disorders; and 6) attempt to trigger erythropoietin production in isolated kidney glomeruli in tissue culture with hypoxia, steroids, prostaglandins and beta-2 agonist drug.
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