Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury

Kidney Int. 2011 Jan;79(1):57-65. doi: 10.1038/ki.2010.377. Epub 2010 Oct 20.


20-Hydroxyeicosatetraenoic acid (20-HETE) production is increased in ischemic kidney tissue and may contribute to ischemia/reperfusion (I/R) injury by mediating vasoconstriction and inflammation. To test this hypothesis, uninephrectomized male Lewis rats were exposed to warm ischemia following pretreatment with either an inhibitor of 20-HETE synthesis (HET0016), an antagonist (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid), an agonist (20-hydroxyeicosa-5(Z),14(Z)-dienoic acid), or vehicle via the renal artery and the kidneys were examined 2 days after reperfusion. Pretreatment with either the inhibitor or the antagonist attenuated I/R-induced renal dysfunction as shown by improved creatinine clearance and decreased plasma urea levels, compared to controls. The inhibitor and antagonist also markedly reduced tubular lesion scores, inflammatory cell infiltration, and tubular epithelial cell apoptosis. Administering the antagonist accelerated the recovery of medullary perfusion, as well as renal medullary and cortical re-oxygenation, during the early reperfusion phase. In contrast, the agonist did not improve renal injury and reversed the beneficial effect of the inhibitor. Thus, 20-HETE generation and its action mediated kidney injury due to I/R. Whether or not these effects are clinically important will need to be tested in appropriate human studies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / metabolism
  • Acute Kidney Injury / pathology
  • Acute Kidney Injury / physiopathology
  • Acute Kidney Injury / prevention & control*
  • Animals
  • Apoptosis / drug effects
  • Creatine / blood
  • Creatine / urine
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 4
  • Epithelial Cells / pathology
  • Hydroxyeicosatetraenoic Acids / agonists
  • Hydroxyeicosatetraenoic Acids / antagonists & inhibitors
  • Hydroxyeicosatetraenoic Acids / biosynthesis*
  • Hydroxyeicosatetraenoic Acids / pharmacology*
  • Kidney Tubules / pathology*
  • Kidney Tubules / physiopathology
  • Models, Animal
  • Rats
  • Rats, Inbred Lew
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control*
  • Statistics, Nonparametric
  • Urea / blood


  • 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid
  • 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid
  • Cyp4a1protein, rat
  • Cytochrome P-450 Enzyme Inhibitors
  • Hydroxyeicosatetraenoic Acids
  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Urea
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 4
  • Creatine