Expression of hypoxia-inducible factor-1alpha and -2alpha in hypoxic and ischemic rat kidneys.
Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis. In vitro, the oxygen-regulated subunits HIF-1alpha and -2alpha are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF response in vivo are largely unknown. High-amplification immunohistochemical analyses were used to study the expression of HIF-1alpha and -2alpha in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1alpha and -2alpha in different renal cell populations. HIF-1alpha was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1alpha colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2alpha was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1alpha and HIF-2alpha is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2alpha in peritubular fibroblasts suggests a role in erythropoietin regulation.
Rosenberger
Christian
C
Department of Nephrology and Medical Intensive Care, Charité, Campus Virchow-Klinikum, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
Mandriota
Stefano
S
Jürgensen
Jan Steffen
JS
Wiesener
Michael S
MS
Hörstrup
Jan H
JH
Frei
Ulrich
U
Ratcliffe
Peter J
PJ
Maxwell
Patrick H
PH
Bachmann
Sebastian
S
Eckardt
Kai-Uwe
KU
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002248:Carbon Monoxide / Q000494:pharmacology; D003035:Cobalt / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D051272:Glucose Transporter Type 1; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007511:Ischemia / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D018962:Phlebotomy; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation; D013194:Staining and Labeling; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D002248:Carbon Monoxide; D003035:Cobalt; D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D010100:Oxygen; D020033:Protein Isoforms; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C497444:Hif1a protein, rat; C495679:Slc2a1 protein, rat; C018021:cobaltous chloride