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

Uwe Hoff, Ivo Lukitsch, Lyubov Chaykovska, Mechthild Ladwig, Cosima Arnold, Vijay L. Manthati, T. Florian Fuller, Wolfgang Schneider, Maik Gollasch, Dominik N. Muller, Bert Flemming, Erdmann Seeliger, Friedrich C. Luft, John R. Falck, Duska Dragun, Wolf Hagen Schunck

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)57-65
Number of pages9
JournalKidney international
Volume79
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • acute kidney injury
  • eicosanoids
  • ischemia/reperfusion

ASJC Scopus subject areas

  • Nephrology

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