Regulation of erythropoietin gene expression depends on two different oxygen-sensing mechanisms

Erythropoietin (Epo), a glycoprotein hormone produced principally in the fe tal kidney and in the adult liver in response to hypoxia, is the prime regu lator of growth and differentiation in erythroid progenitor cells, The regu lation of Epo gene expression is not fully understood, but two mechanisms h ave been proposed. One involves the participation of a heme protein capable of reversible oxygenation and the other depends on the intracellular conce ntration of reactive oxygen species (ROS), assumed to be a function of pO(2 ). We have investigated the production of Epo in response to three stimuli, hypoxia, cobalt chloride, and the iron chelator desferrioxamine, in Hep3B cells. As expected, hypoxia caused a marked rise in Epo production. When th e cells were exposed to the paired stimuli of hypoxia and cobalt no further increase was found. In contrast, chelation of iron under hypoxic condition s markedly enhanced Epo production, suggesting that the two stimuli act by separate pathways, The addition of carbon monoxide inhibited hypoxia-induce d Epo production, independent of desferrioxamine concentration. Taken toget her these data support the concept that pO(2) and ROS are sensed independen tly. (C) 1999 Academic Press.