Erythropoietin and microvascular diabetic complications

Abstract

When recombinant human erythropoietin (EPO) became available for clinical use, the hormone was considered as a specific erythropoietic growth factor and as a more or less unique molecule, since its endogenous production increases in response to reduced oxygen availability. Subsequently, we have witnessed a revolutionary increase in knowledge about the highly conserved ability of virtually all cells to sense oxygen and to translate reductions in oxygen availability into specific patterns of gene expression. This hypoxia response is to a large extent mediated by hypoxia-inducible transcription factors (HIF). EPO is the prime example for a hypoxia-inducible HIF target gene, but more than 100 additional genes have meanwhile also been identified as HIF targets, including genes involved in new vessel formation and anaerobic metabolism. In general, the activation of the hypoxia pathway stimulates responses that increase either oxygen availability or hypoxia tolerance [1]. Consistent with this broader perspective of oxygen sensing and tissue responsiveness to changes in oxygenation, EPOhasmeanwhilealsobeenfoundtohaveactionsbeyond stimulationofredcellprecursors,includingpro-angiogenic andcellprotectivefunctions.HighdosesofEPOconveytissue protection in experimental models of ischaemic brain and kidney injury, and trials testing the clinical utility of such effects are underway. Moreover, low levels of EPOgene expression have been found in various tissues other than liver and kidneys, the two organs that are responsible for the synthesis of circulating EPO. In combination, these findings suggest that EPO—in addition to its function as an erythropoietichormone—canalsoactasaparacrinegrowth factor. However, the pathophysiological relevance of EPO effectsoutsidethebonemarrowremainspoorlyunderstood.