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Renal ischemia/reperfusion injury in soluble epoxide hydrolase-deficient mice

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Item Type:Article
Title:Renal ischemia/reperfusion injury in soluble epoxide hydrolase-deficient mice
Creators Name:Zhu, Y. and Blum, M. and Hoff, U. and Wesser, T. and Fechner, M. and Westphal, C. and Gürgen, D. and Catar, R.A. and Philippe, A. and Wu, K. and Bubalo, G. and Rothe, M. and Weldon, S.M. and Dragun, D. and Schunck, W.H.
Abstract:Aim: 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP)-dependent eicosanoids that play opposite roles in the regulation of vascular tone, inflammation, and apoptosis. 20-HETE aggravates, whereas EETs ameliorate ischemia/reperfusion (I/R)-induced organ damage. EETs are rapidly metabolized to dihydroxyeicosatrienoic acids (DHETs) by the soluble epoxide hydrolase (sEH). We hypothesized that sEH gene (EPHX2) deletion would increase endogenous EET levels and thereby protect against I/R-induced acute kidney injury (AKI). Methods: Kidney damage was evaluated in male wildtype (WT) and sEH-knockout (KO)-mice that underwent 22-min renal ischemia followed by two days of reperfusion. CYP-eicosanoids were analyzed by liquid chromatography tandem mass spectrometry. Results: Contrary to our initial hypothesis, renal function declined more severely in sEH-KO mice as indicated by higher serum creatinine and urea levels. The sEH-KO-mice also featured stronger tubular lesion scores, tubular apoptosis, and inflammatory cell infiltration. Plasma and renal EET/DHET-ratios were higher in sEH-KO than WT mice, thus confirming the expected metabolic consequences of sEH deficiency. However, CYP-eicosanoid profiling also revealed that renal, but not plasma and hepatic, 20-HETE levels were significantly increased in sEH-KO compared to WT mice. In line with this finding, renal expression of Cyp4a12a, the murine 20-HETE-generating CYP-enzyme, was up-regulated both at the mRNA and protein level, and Cyp4a12a immunostaining was more intense in the renal arterioles of sEH-KO compared with WT mice. Conclusion: These results indicate that the potential beneficial effects of reducing EET degradation were obliterated by a thus far unknown mechanism leading to kidney-specific up-regulation of 20-HETE formation in sEH-KO-mice.
Keywords:Cytochrome P-450 Enzyme System, Epoxide Hydrolases, Hydroxyeicosatetraenoic Acids, Kidney, Knockout Mice, Liquid Chromatography, Oxylipins, Reperfusion Injury, Tandem Mass Spectrometry, Animals, Mice
Source:PLoS ONE
Publisher:Public Library of Science
Page Range:e0145645
Date:4 January 2016
Official Publication:https://doi.org/10.1371/journal.pone.0145645
PubMed:View item in PubMed

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