Non-hypoxic induction of HIF-3alpha 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-1alpha, -2alpha, -3alpha, -1beta, and of the target gene GLUT-1 was determined. Distribution of HIF-3alpha proteins was examined by immunohistochemistry. Both, insulin and 2-DG resulted in a widespread increase in HIF-3alpha mRNA. HIF-2alpha 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-3alpha. Functional significance of HIF induction was reflected in enhancement of GLUT-1 mRNA. Transcriptional up-regulation of HIF-3alpha 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.
Heidbreder
Marc
M
Institute of Experimental and Clinical Pharmacology and Toxicology, University of Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany. heidbred@medinf.mu-luebeck.de
Qadri
Fatimunnisa
F
Jöhren
Olaf
O
Dendorfer
Andreas
A
Depping
Reinhard
R
Fröhlich
Frederike
F
Wagner
Klaus F
KF
Dominiak
Peter
P
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D012097:Repressor Proteins; D014018:Tissue Distribution; D014157:Transcription Factors / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C444643:Hif3a protein, mouse; D007328:Insulin; D012097:Repressor Proteins; D014157:Transcription Factors; D003847:Deoxyglucose