Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury.
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.
Hoff
Uwe
U
Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
Lukitsch
Ivo
I
Chaykovska
Lyubov
L
Ladwig
Mechthild
M
Arnold
Cosima
C
Manthati
Vijay L
VL
Fuller
T Florian
TF
Schneider
Wolfgang
W
Gollasch
Maik
M
Muller
Dominik N
DN
Flemming
Bert
B
Seeliger
Erdmann
E
Luft
Friedrich C
FC
Falck
John R
JR
Dragun
Duska
D
Schunck
Wolf-Hagen
WH
D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003401:Creatine / Q000097:blood / Q000652:urine; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D004847:Epithelial Cells / Q000473:pathology; D006893:Hydroxyeicosatetraenoic Acids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology*; D007684:Kidney Tubules / Q000473:pathology* / Q000503:physiopathology; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018709:Statistics, Nonparametric; D014508:Urea / Q000097:blood
C494665:20-hydroxyeicosa-5(Z),14(Z)-dienoic acid; C494667:20-hydroxyeicosa-6(Z),15(Z)-dienoic acid; C465387:Cyp4a1protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D014508:Urea; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; D003401:Creatine