A biologic role of HIF-1 in the renal medulla

Kidney Int. 2005 Apr;67(4):1428-39. doi: 10.1111/j.1523-1755.2005.00220.x.


Background: Activation of hypoxia-inducible factor-1 (HIF-1) is the primary defensive mechanism against hypoxia. HIF-1 activation generally occurs in pathologic disruption of tissue oxygenation. However, a biologic role of HIF-1 in the medulla of the kidney, which is considered perpetually hypoxic under physiologic conditions due to its unique circulation, remains to be elucidated.

Methods: The expression of HIF-1alpha was detected by immunohistochemical analysis. Functional studies of HIF in medulla were carried out by gene transfer of various plasmids by retrograde injection via ureter.

Results: Our immunohistochemical analysis detected HIF-1alpha in the inner stripe and the inner medulla of normal rats. Water deprivation increased the number of HIF-1alpha-positive cells, which may be mediated by an increase in medullar workload and a decrease in local blood flow. To perform functional studies, we performed gene transfer. Efficient expression of the transgene was confirmed using an enhanced green fluorescent protein (E-GFP) expressing vector. Our histologic and immunoblotting analysis detected the transgene product at the inner medulla and the inner stripe 48 hours after injection. Administration of negative-dominant HIF induced severe damage in the medulla of normal rats. In contrast, gene transfer of constitutively active HIF (HIF/VP16) induced expression of various HIF-regulated genes and protected the medulla against ischemic insults.

Conclusion: Our studies demonstrated a crucial role of HIF in the renal medulla under normal and hypoxic circumstances.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blood Urea Nitrogen
  • Cell Hypoxia / physiology
  • DNA Primers
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Gene Transfer Techniques
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Kidney Medulla / cytology
  • Kidney Medulla / physiology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology*
  • Polymerase Chain Reaction
  • Rats
  • Rats, Sprague-Dawley
  • Transcription Factors / analysis
  • Transcription Factors / genetics
  • Transcription Factors / physiology*


  • DNA Primers
  • DNA-Binding Proteins
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors
  • Green Fluorescent Proteins