Erythropoietin production: evidence for multiple oxygen sensing pathways

The production of erythropoietin (Epo), the glycoprotein hormone which cont rols red blood cell formation, is regulated by feedback mechanisms sensing tissue oxygenation. The mechanism of the putative oxygen sensor has yet to be elucidated. There is evidence that at least two pathways participate in hypoxia signal transduction. One appears to involve a specific haem protein , and a second implicates reactive oxygen species (ROS). Iron catalyses the generation of intracellular ROS and therefore alters the cellular redox st ate. We have investigated the effect of modulating intracellular iron conte nt on Epo production in Hep 3B cells. Iron chelation stimulates Epo product ion at 20% O-2 and enhances Epo production at 1% O-2, but it has no additiv e effect on cobalt-induced Epo production. Excess molar iron inhibited Epo production in response to hypoxia, desferrioxamine (DFO) and cobalt chlorid e and inhibited the DFO-enhancing effect of hypoxia-induced Epo production. We found that sulphydryl oxidising agents exert a differential inhibitory effect on hypoxia-induced versus DFO-induced Epo production, providing furt her evidence that multiple pathways of oxygen sensing exist.