Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury

Kevin R. Regner; Anna Zuk; Scott K. Van Why; Brian D. Shames; Robert P. Ryan; J R Falck; Vijay L. Manthati; Meghan E. McMullen; Steven R. Ledbetter; Richard J. Roman

doi:10.1038/ki.2008.600

Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury

Kevin R. Regner, Anna Zuk, Scott K. Van Why, Brian D. Shames, Robert P. Ryan, J R Falck, Vijay L. Manthati, Meghan E. McMullen, Steven R. Ledbetter, Richard J. Roman

Biochemistry

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

74 Scopus citations

Abstract

While it is known that the arachidonic acid metabolite 20- hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemic injury in the heart and brain, its role in kidney injury is unclear. Here we determined the effects on ischemia-reperfusion injury of the 20-HETE analogues, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid (5,14-20-HEDE), and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE), and of the inhibitor of 20-HETE synthesis N-hydroxy-N-(4-butyl-2 methylphenyl) formamidine (HET0016). Using Sprague-Dawley rats we found that while treatment with the inhibitor exacerbated renal injury, infusion of both 5,14-20-HEDE and 5,14-20-HEDGE significantly attenuated injury when compared to vehicle or inhibitor-treated rats. Medullary blood flow, measured by laser-Doppler flowmetry, decreased to half of the baseline one hour after reperfusion in the control rats, but 5,14-20-HEDGE completely prevented this. Treatment of control animals with 5,14-20-HEDGE increased urine output and sodium excretion without altering their mean arterial pressure or glomerular filtration rate. Our results suggest that 20-HETE analogues protect the kidney from ischemia-reperfusion injury by inhibiting renal tubular sodium transport and preventing the post-ischemic fall in medullary blood flow. Analogues of 20-HETE may be useful in the treatment of acute ischemic kidney injury.

Original language	English (US)
Pages (from-to)	511-517
Number of pages	7
Journal	Kidney international
Volume	75
Issue number	5
DOIs	https://doi.org/10.1038/ki.2008.600
State	Published - Mar 2009

Keywords

20-HETE
Acute kidney injury
Acute renal failure
HET0016
Ischemia-reperfusion

ASJC Scopus subject areas

Nephrology

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10.1038/ki.2008.600

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@article{532e394873504368b326d756ef6fd947,

title = "Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury",

abstract = "While it is known that the arachidonic acid metabolite 20- hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemic injury in the heart and brain, its role in kidney injury is unclear. Here we determined the effects on ischemia-reperfusion injury of the 20-HETE analogues, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid (5,14-20-HEDE), and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE), and of the inhibitor of 20-HETE synthesis N-hydroxy-N-(4-butyl-2 methylphenyl) formamidine (HET0016). Using Sprague-Dawley rats we found that while treatment with the inhibitor exacerbated renal injury, infusion of both 5,14-20-HEDE and 5,14-20-HEDGE significantly attenuated injury when compared to vehicle or inhibitor-treated rats. Medullary blood flow, measured by laser-Doppler flowmetry, decreased to half of the baseline one hour after reperfusion in the control rats, but 5,14-20-HEDGE completely prevented this. Treatment of control animals with 5,14-20-HEDGE increased urine output and sodium excretion without altering their mean arterial pressure or glomerular filtration rate. Our results suggest that 20-HETE analogues protect the kidney from ischemia-reperfusion injury by inhibiting renal tubular sodium transport and preventing the post-ischemic fall in medullary blood flow. Analogues of 20-HETE may be useful in the treatment of acute ischemic kidney injury.",

keywords = "20-HETE, Acute kidney injury, Acute renal failure, HET0016, Ischemia-reperfusion",

author = "Regner, {Kevin R.} and Anna Zuk and {Van Why}, {Scott K.} and Shames, {Brian D.} and Ryan, {Robert P.} and Falck, {J R} and Manthati, {Vijay L.} and McMullen, {Meghan E.} and Ledbetter, {Steven R.} and Roman, {Richard J.}",

note = "Funding Information: This work was partially supported by Grants HL36279, HL29546, DK38226, and GM31278 from the National Institutes of Health; the Robert A. Welch Foundation; and a Mentored Clinical/Translational Research Award from the Clinical and Translational Science Institute at the Medical College of Wisconsin. We thank Averia Steinman for assistance with the mass spectrometry analysis and Denise McCabe and Christopher Chaber for assistance with the TUNEL analysis.",

year = "2009",

month = mar,

doi = "10.1038/ki.2008.600",

language = "English (US)",

volume = "75",

pages = "511--517",

journal = "Kidney international",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "5",

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AU - Regner, Kevin R.

AU - Zuk, Anna

AU - Van Why, Scott K.

AU - Shames, Brian D.

AU - Ryan, Robert P.

AU - Falck, J R

AU - Manthati, Vijay L.

AU - McMullen, Meghan E.

AU - Ledbetter, Steven R.

AU - Roman, Richard J.

N1 - Funding Information: This work was partially supported by Grants HL36279, HL29546, DK38226, and GM31278 from the National Institutes of Health; the Robert A. Welch Foundation; and a Mentored Clinical/Translational Research Award from the Clinical and Translational Science Institute at the Medical College of Wisconsin. We thank Averia Steinman for assistance with the mass spectrometry analysis and Denise McCabe and Christopher Chaber for assistance with the TUNEL analysis.

PY - 2009/3

Y1 - 2009/3

N2 - While it is known that the arachidonic acid metabolite 20- hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemic injury in the heart and brain, its role in kidney injury is unclear. Here we determined the effects on ischemia-reperfusion injury of the 20-HETE analogues, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid (5,14-20-HEDE), and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE), and of the inhibitor of 20-HETE synthesis N-hydroxy-N-(4-butyl-2 methylphenyl) formamidine (HET0016). Using Sprague-Dawley rats we found that while treatment with the inhibitor exacerbated renal injury, infusion of both 5,14-20-HEDE and 5,14-20-HEDGE significantly attenuated injury when compared to vehicle or inhibitor-treated rats. Medullary blood flow, measured by laser-Doppler flowmetry, decreased to half of the baseline one hour after reperfusion in the control rats, but 5,14-20-HEDGE completely prevented this. Treatment of control animals with 5,14-20-HEDGE increased urine output and sodium excretion without altering their mean arterial pressure or glomerular filtration rate. Our results suggest that 20-HETE analogues protect the kidney from ischemia-reperfusion injury by inhibiting renal tubular sodium transport and preventing the post-ischemic fall in medullary blood flow. Analogues of 20-HETE may be useful in the treatment of acute ischemic kidney injury.

AB - While it is known that the arachidonic acid metabolite 20- hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemic injury in the heart and brain, its role in kidney injury is unclear. Here we determined the effects on ischemia-reperfusion injury of the 20-HETE analogues, 20-hydroxyeicosa-5(Z), 14(Z)-dienoic acid (5,14-20-HEDE), and N-[20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE), and of the inhibitor of 20-HETE synthesis N-hydroxy-N-(4-butyl-2 methylphenyl) formamidine (HET0016). Using Sprague-Dawley rats we found that while treatment with the inhibitor exacerbated renal injury, infusion of both 5,14-20-HEDE and 5,14-20-HEDGE significantly attenuated injury when compared to vehicle or inhibitor-treated rats. Medullary blood flow, measured by laser-Doppler flowmetry, decreased to half of the baseline one hour after reperfusion in the control rats, but 5,14-20-HEDGE completely prevented this. Treatment of control animals with 5,14-20-HEDGE increased urine output and sodium excretion without altering their mean arterial pressure or glomerular filtration rate. Our results suggest that 20-HETE analogues protect the kidney from ischemia-reperfusion injury by inhibiting renal tubular sodium transport and preventing the post-ischemic fall in medullary blood flow. Analogues of 20-HETE may be useful in the treatment of acute ischemic kidney injury.

KW - 20-HETE

KW - Acute kidney injury

KW - Acute renal failure

KW - HET0016

KW - Ischemia-reperfusion

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DO - 10.1038/ki.2008.600

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JO - Kidney international

JF - Kidney international

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ER -

Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury

Abstract

Keywords

ASJC Scopus subject areas

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