PMID- 26727266 OWN - NLM STAT- MEDLINE DCOM- 20160708 LR - 20191210 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 11 IP - 1 DP - 2016 TI - Renal Ischemia/Reperfusion Injury in Soluble Epoxide Hydrolase-Deficient Mice. PG - e0145645 LID - 10.1371/journal.pone.0145645 [doi] LID - e0145645 AB - 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. FAU - Zhu, Ye AU - Zhu Y AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. AD - The fifth affiliated hospital of Sun Yat-sen University, Guangdong Province, Zhuhai, China. FAU - Blum, Maximilian AU - Blum M AD - Max Delbrueck Center for Molecular Medicine, Berlin, Germany. FAU - Hoff, Uwe AU - Hoff U AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. FAU - Wesser, Tim AU - Wesser T AD - Max Delbrueck Center for Molecular Medicine, Berlin, Germany. FAU - Fechner, Mandy AU - Fechner M AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. FAU - Westphal, Christina AU - Westphal C AD - Max Delbrueck Center for Molecular Medicine, Berlin, Germany. FAU - Gurgen, Dennis AU - Gurgen D AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. FAU - Catar, Rusan Ali AU - Catar RA AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. FAU - Philippe, Aurelie AU - Philippe A AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. FAU - Wu, Kaiyin AU - Wu K AD - Institute of Pathology, Charite Campus Mitte, 10117, Berlin, Germany. FAU - Bubalo, Gordana AU - Bubalo G AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. FAU - Rothe, Michael AU - Rothe M AD - Lipidomix GmbH, Berlin, Germany. FAU - Weldon, Steven M AU - Weldon SM AD - Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, United States of America. FAU - Dragun, Duska AU - Dragun D AD - Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charite Medical Faculty, Berlin, Germany. FAU - Schunck, Wolf-Hagen AU - Schunck WH AD - Max Delbrueck Center for Molecular Medicine, Berlin, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160104 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Hydroxyeicosatetraenoic Acids) RN - 0 (Oxylipins) RN - 79551-86-3 (20-hydroxy-5,8,11,14-eicosatetraenoic acid) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.14.1 (Cyp4a12a protein, mouse) RN - EC 1.14.14.1 (Cytochrome P450 Family 4) RN - EC 3.3.2.- (Epoxide Hydrolases) SB - IM MH - Animals MH - Chromatography, Liquid MH - Cytochrome P-450 Enzyme System/metabolism MH - Cytochrome P450 Family 4 MH - Epoxide Hydrolases/*genetics MH - Hydroxyeicosatetraenoic Acids/biosynthesis MH - Kidney/*blood supply/enzymology MH - Male MH - Mice MH - Mice, Knockout MH - Oxylipins/metabolism MH - Reperfusion Injury/*enzymology MH - Tandem Mass Spectrometry PMC - PMC4699807 COIS- Competing Interests: The authors have the following interests: SMW is employed by Boehringer Ingelheim Pharmaceuticals Inc. MR is employed by Lipidomix GmbH. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors. EDAT- 2016/01/05 06:00 MHDA- 2016/07/09 06:00 PMCR- 2016/01/04 CRDT- 2016/01/05 06:00 PHST- 2015/07/17 00:00 [received] PHST- 2015/12/07 00:00 [accepted] PHST- 2016/01/05 06:00 [entrez] PHST- 2016/01/05 06:00 [pubmed] PHST- 2016/07/09 06:00 [medline] PHST- 2016/01/04 00:00 [pmc-release] AID - PONE-D-15-31351 [pii] AID - 10.1371/journal.pone.0145645 [doi] PST - epublish SO - PLoS One. 2016 Jan 4;11(1):e0145645. doi: 10.1371/journal.pone.0145645. eCollection 2016.