title: Renal Ischemia/Reperfusion Injury in Soluble Epoxide Hydrolase-Deficient Mice.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.|The fifth affiliated hospital of Sun Yat-sen University, Guangdong Province, Zhuhai, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Blum
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hoff
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Wesser
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Fechner
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Westphal
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Gürgen
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
authors.forename: Rusan Ali
authors.initials: RA
authors.lastname: Catar
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Philippe
authors.affiliation: Institute of Pathology, Charité Campus Mitte, 10117, Berlin, Germany.
authors.forename: Kaiyin
authors.initials: K
authors.lastname: Wu
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
authors.forename: Gordana
authors.initials: G
authors.lastname: Bubalo
authors.affiliation: Lipidomix GmbH, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Weldon
authors.affiliation: Nephrology and Intensive Care Medicine, Campus Virchow and Center for Cardiovascular Research, Charité Medical Faculty, Berlin, Germany.
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D004851:Epoxide Hydrolases / Q000235:genetics*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D007668:Kidney / Q000098:blood supply* / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054883:Oxylipins / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology*; D053719:Tandem Mass Spectrometry
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D054883:Oxylipins; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; C493210:Cyp4a12a protein, mouse; D000072470:Cytochrome P450 Family 4; D004851:Epoxide Hydrolases