Non-hypoxic induction of HIF-3α by 2-deoxy-d-glucose and insulin

Hypoxia-inducible factors (HIFs) are key mediators of cellular adaptation to hypoxia, but also respond to non-hypoxic stimuli. To clarify involvement in metabolic disturbances, HIFs were characterised in rats subjected to insulin-induced hypoglycaemia or cellular glucoprivation provoked by 2-deoxy-d-glucose (2-DG). Using real-time qPCR, organ-specific expression of HIF-1α, -2α, -3α, -1β, and of the target gene GLUT-1 was determined. Distribution of HIF-3α proteins was examined by immunohistochemistry. Both, insulin and 2-DG resulted in a widespread increase in HIF-3α mRNA. HIF-2α mRNA increased in lung and heart after 2-DG only, whereas other HIFs remained unaffected. A pronounced increase of protein levels in cerebral cortex was observed for HIF-3α. Functional significance of HIF induction was reflected in enhancement of GLUT-1 mRNA. Transcriptional up-regulation of HIF-3α represents a typical response to in vivo hypoglycaemia and glucoprivation. These data suggest an involvement of the HIF system in metabolic derangements as for instance caused by diabetes.