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

doi:10.1038/ki.2010.377

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

Biochemistry

Research output: Contribution to journal › Article › peer-review

64 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 language	English (US)
Pages (from-to)	57-65
Number of pages	9
Journal	Kidney international
Volume	79
Issue number	1
DOIs	https://doi.org/10.1038/ki.2010.377
State	Published - Jan 2011

Keywords

acute kidney injury
eicosanoids
ischemia/reperfusion

ASJC Scopus subject areas

Nephrology

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10.1038/ki.2010.377

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Hoff, U., Lukitsch, I., Chaykovska, L., Ladwig, M., Arnold, C., Manthati, V. L., Fuller, T. F., Schneider, W., Gollasch, M., Muller, D. N., Flemming, B., Seeliger, E., Luft, F. C., Falck, J. R., Dragun, D., & Schunck, W. H. (2011). Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury. Kidney international, 79(1), 57-65. https://doi.org/10.1038/ki.2010.377

Hoff, U, Lukitsch, I, Chaykovska, L, Ladwig, M, Arnold, C, Manthati, VL, Fuller, TF, Schneider, W, Gollasch, M, Muller, DN, Flemming, B, Seeliger, E, Luft, FC, Falck, JR, Dragun, D & Schunck, WH 2011, 'Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury', Kidney international, vol. 79, no. 1, pp. 57-65. https://doi.org/10.1038/ki.2010.377

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

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.",

keywords = "acute kidney injury, eicosanoids, ischemia/reperfusion",

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

note = "Funding Information: We thank Christel Andr{\'e}e and Ramona Zummach for excellent technical assistance. We are grateful to Michael Rothe and Katrin Blossey, Lipidomix GmbH (Berlin, Germany) for performing the liquid chromatography tandem mass spectrometry analysis. This study was supported in part by grants of the Werner Jackst{\"a}dt-Stiftung, Wuppertal, Germany to UH, of the BMWi, Germany (KF0568201UL7) to DD and WHS, and by USPHS NIH (GM31278) and the Robert A. Welch Foundation to JRF.",

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doi = "10.1038/ki.2010.377",

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AU - Hoff, Uwe

AU - Lukitsch, Ivo

AU - Chaykovska, Lyubov

AU - Ladwig, Mechthild

AU - Arnold, Cosima

AU - Manthati, Vijay L.

AU - Fuller, T. Florian

AU - Schneider, Wolfgang

AU - Gollasch, Maik

AU - Muller, Dominik N.

AU - Flemming, Bert

AU - Seeliger, Erdmann

AU - Luft, Friedrich C.

AU - Falck, John R.

AU - Dragun, Duska

AU - Schunck, Wolf Hagen

N1 - Funding Information: We thank Christel Andrée and Ramona Zummach for excellent technical assistance. We are grateful to Michael Rothe and Katrin Blossey, Lipidomix GmbH (Berlin, Germany) for performing the liquid chromatography tandem mass spectrometry analysis. This study was supported in part by grants of the Werner Jackstädt-Stiftung, Wuppertal, Germany to UH, of the BMWi, Germany (KF0568201UL7) to DD and WHS, and by USPHS NIH (GM31278) and the Robert A. Welch Foundation to JRF.

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N2 - 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.

AB - 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.

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

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