Abstract
Acute kidney injury is associated with a significant inflammatory response that has been the target of renoprotection strategies. Epoxyeicosatrienoic acids (EETs) are anti-inflammatory cytochrome P450-derived eicosanoids that are abundantly produced in the kidney and metabolized by soluble epoxide hydrolase (sEH; Ephx2) to less active dihydroxyeicosatrienoic acids. Genetic disruption of Ephx2 and chemical inhibition of sEH were used to test whether the anti-inflammatory effects of EETs, and other lipid epoxide substrates of sEH, afford protection against cisplatin-induced nephrotoxicity. EET hydrolysis was significantly reduced in Ephx2(−/−) mice and was associated with an attenuation of cisplatin-induced increases in serum urea nitrogen and creatinine levels. Histological evidence of renal tubular damage and neutrophil infiltration was also reduced in the Ephx2(−/−) mice. Likewise, cisplatin had no effect on renal function, neutrophil infiltration, or tubular structure and integrity in mice treated with the potent sEH inhibitor 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea) (AR9273). Consistent with the ability of EETs to interfere with nuclear factor-κB (NF-κB) signaling, the observed renoprotection was associated with attenuation of renal NF-κB activity and corresponding decreases in the expression of tumor necrosis factor (TNF) α, TNF receptor (TNFR) 1, TNFR2, and intercellular adhesive molecule-1 before the detection of tubular injury. These data suggest that EETs or other fatty acid epoxides can attenuate cisplatin-induced kidney injury and sEH inhibition is a novel renoprotective strategy.
Footnotes
This work was supported by the University of California Discovery Program [Grant Bio06-1-576]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK084147]; and Arête Therapeutics. J.M. was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Training Grant T32-GM007175].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- EET
- epoxyeicosatrienoic acid
- DHET
- dihydroxyeicosatrienoic acid
- P450
- cytochrome P450
- sEH
- soluble epoxide hydrolase
- NF-κB
- nuclear factor-κB
- TNFα
- tumor necrosis factor α
- TNFR
- TNFα receptor
- ICAM-1
- intercellular adhesive molecule-1
- AR9273
- 1-adamantan-1-yl-3-(1-methylsulfonyl-piperidin-4-yl-urea)
- EpOME
- epoxyoctadecenoic acid
- DiHOME
- dihydroxyoctadecenoic acid
- Kim-1
- kidney injury molecule-1
- PAS
- periodic acid-Schiff
- LC/MS/MS
- liquid chromatography-tandem mass spectrometry
- Gapdh
- glyceraldehyde-3-phosphate dehydrogenase
- hpf
- high-power fields
- EIA
- enzyme immunoassay
- TUNEL
- terminal deoxynucleotidyl transferase dUTP nick-end labeling
- PCR
- polymerase chain reaction
- DAPI
- 4,6-diamidino-2-phenylindole.
- Received December 27, 2011.
- Accepted March 12, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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