title: Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia.
abstract: BACKGROUND
  Medullary hypoxia is believed to play an important role in the pathogenesis of acute renal failure (ARF). Hypoxia-inducible transcription factors (HIF) are recognized as master regulators of hypoxic adaptation, but little is known about their role in renal disease.
  
  
  METHODS
  A multi-insult rat model of ARF combining the application of contrast medium with nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition was used to study chronology and distribution of the oxygen regulated HIF isoforms HIF-1alpha and HIF-2alpha in comparison with the hypoxia-marker pimonidazole between 10 minutes and 48 hours after injury induction. Treatment with furosemide was used to study HIF expression under conditions of ameliorated tissue injury.
  
  
  RESULTS
  Contrast medium in combination with NOS and COX inhibition resulted in widespread induction of HIF in the outer and inner medulla that was initiated within 10 minutes, reached the highest levels at 2 hours and diminished 8 hours to 24 hours thereafter. HIF isoforms were expressed in a cell type-specific fashion: HIF-1alpha in tubular and HIF-2alpha in interstitial and endothelial cells. The degree of HIF-1alpha accumulation varied between nephron segments, being much stronger in collecting ducts than in medullary thick ascending limb of the loop of Henle (mTAL). Comparison with pimonidazole staining and the effect of furosemide indicated that HIF induction in mTAL is maximal with moderate hypoxia and declines with increasing severity of hypoxia.
  
  
  CONCLUSIONS
  A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury.
authors.affiliation: Department of Nephrology and Medical Intensive Care, Charité University Medicine, Berlin, Germany. chrosenbe@aol.com
authors.forename: Christian
authors.initials: C
authors.lastname: Rosenberger
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Heyman
authors.forename: Seymour
authors.initials: S
authors.lastname: Rosen
authors.forename: Ahuva
authors.initials: A
authors.lastname: Shina
authors.forename: Marina
authors.initials: M
authors.lastname: Goldfarb
authors.forename: Wanja
authors.initials: W
authors.lastname: Griethe
authors.forename: Ulrich
authors.initials: U
authors.lastname: Frei
authors.forename: Petra
authors.initials: P
authors.lastname: Reinke
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bachmann
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015687:Cell Hypoxia; D005665:Furosemide / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis; D051547:Heme Oxygenase-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007213:Indomethacin / Q000494:pharmacology; D007483:Iothalamic Acid / Q000494:pharmacology; D008297:Male; D009593:Nitroimidazoles / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015534:Trans-Activators / Q000032:analysis / Q000096:biosynthesis*; D014157:Transcription Factors / Q000032:analysis / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005665:Furosemide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007213:Indomethacin; D007483:Iothalamic Acid; D009593:Nitroimidazoles; D015534:Trans-Activators; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C033815:pimonidazole