title: Impact of soluble epoxide hydrolase inhibition on early kidney damage in hyperglycemic overweight mice.
abstract: This study addressed the hypothesis that inhibition of the EETs degrading enzyme soluble epoxide hydrolase affords renal protection in the early stage of diabetic nephropathy. The renal effects of the sEH inhibitor t-AUCB (10mg/l in drinking water) were compared to those of the sulfonylurea glibenclamide (80mg/l), both administered for 8 weeks in FVB mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat) and non-treated HFD mice served as controls. Compared with non-treated HFD mice, HFD mice treated with t-AUCB had a decreased EET degradation, as shown by their higher plasma EETs-to-DHETs ratio, and an increased EET production, as shown by the increase in EETs+DHETs levels, which was associated with induction of CYP450 epoxygenase expression. Both agents similarly reduced fasting glycemia but only t-AUCB prevented the increase in the urinary albumine-to-creatinine ratio in HFD mice. Histopathological analysis showed that t-AUCB reduced renal inflammation, which was associated with an increased mRNA expression of the NFκB inhibitor Iκ≡ and related decrease in MCP-1, COX2 and VCAM-1 expressions. Finally, there was a marginally significant increase in reactive oxygen species production in HFD mice, together with an enhanced NOX2 expression. Both agents did not modify these parameters but t-AUCB increased the expression of the antioxidant enzyme superoxide dismutase 1. These results demonstrate that, independently from its glucose-lowering effect, sEH inhibition prevents microalbuminuria and renal inflammation in overweight hyperglycemic mice, suggesting that this pharmacological strategy could be useful in the management of diabetic nephropathy.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Clothilde
authors.initials: C
authors.lastname: Roche
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Nephrology, Rouen University Hospital, Rouen, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Guerrot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Najah
authors.initials: N
authors.lastname: Harouki
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Pharmacology, Rouen University Hospital, Rouen, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duflot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Besnier
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rémy-Jouet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Sylvanie
authors.initials: S
authors.lastname: Renet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Dumesnil
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Lejeune
authors.affiliation: Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, Davis, CA, United States.
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Pharmacology, Rouen University Hospital, Rouen, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Department of Pharmacology, Rouen University Hospital, Rouen, France. Electronic address: jeremy.Bellien@chu-rouen.fr.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellien
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D005215:Fasting / Q000097:blood; D005905:Glyburide / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008820:Mice, Obese; D009929:Organ Size / Q000187:drug effects; D050177:Overweight / Q000097:blood* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D012995:Solubility; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D001786:Blood Glucose; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D014508:Urea; D004851:Epoxide Hydrolases; D005905:Glyburide
keywords: Diabetes; Diabetic nephropathy; Renal inflammation; Soluble epoxide hydrolase