Regulation of Erythropoietin Expression in the Nervous System: The Hypoxia Inducible Factor

Abstract

Hypoxia is associated with a variety of CNS diseases including stroke, traumatic brain injury and spinal cord injury. Induction of erythropoietin (EPO) is a physiological response to hypoxia in oxygen-deprived tissues. Hypoxia-induced epo gene expression is regulated by the transcriptional activator hypoxia inducible factor (HIF). The epo gene contains a HIF binding site in its 3′ untranslated region, and its expression is upregulated concomitantly with HIF activation in a variety of cell culture models as well as in the brains of rodents exposed to hypoxia or pharmacological agents that mimic hypoxia, such as iron chelators and cobalt chloride. Since HIF is a master regulator of oxygen homeostasis in all mammalian cells and controls the expression of a variety of genes required for cellular adaptation to hypoxia (including epo), this review covers the current knowledge about the oxygen sensing mechanism that regulates the activation of HIF under hypoxic conditions. An important challenge for the future is to determine how modulating the activation of HIF with the subsequent expression of EPO can be beneficial for neural survival under stress conditions that involve hypoxia.