title: Deletion of soluble epoxide hydrolase gene improves renal endothelial function and reduces renal inflammation and injury in streptozotocin-induced type 1 diabetes.
abstract: Studies suggest that soluble epoxide hydrolase (sEH) inhibition reduces end-organ damage in cardiovascular diseases. We hypothesize that sEH gene (Ephx2) knockout (KO) improves endothelial function and reduces renal injury in streptozotocin-induced diabetes. After 6 wk of diabetes, afferent arteriolar relaxation to acetylcholine was impaired in diabetic wild-type (WT) mice, as the maximum relaxation was 72% of baseline diameter in the WT but only 31% in the diabetic mice. Ephx2 KO improved afferent arteriolar relaxation to acetylcholine in diabetes as maximum relaxation was 58%. Urinary monocyte chemoattractant protein-1 (MCP-1) excretion significantly increased in diabetic WT mice compared with control (868 ± 195 vs. 31.5 ± 7 pg/day), and this increase was attenuated in diabetic Ephx2 KO mice (420 ± 98 pg/day). The renal phospho-IKK-to-IKK ratio and nuclear factor-κB were significantly decreased, and hemeoxygenase-1 (HO-1) expression increased in diabetic Ephx2 KO compared with diabetic WT mice. Renal NADPH oxidase and urinary thiobarbituric acid reactive substances excretion were reduced in diabetic Ephx2 KO compared with diabetic WT mice. Albuminuria was also elevated in diabetic WT mice compared with control (170 ± 43 vs. 37 ± 13 μg/day), and Ephx2 KO reduced this elevation (50 ± 15 μg/day). Inhibition of sEH using trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) also reduced renal inflammation and injury in diabetic WT mice. Furthermore, inhibition of HO with stannous mesoporphyrin negated the reno-protective effects of tAUCB or Ephx2 KO during diabetes. These data demonstrate that Ephx2 KO improves endothelial function and reduces renal injury during diabetes. Additionally, our data also suggest that activation of HO-1 contributes to improved renal injury in diabetic Ephx2 KO mice.
authors.affiliation: Department of Oral Biology, Georgia Health Sciences University, Augusta, Georgia 30912, USA. aelmarakby@georgiahealth.edu
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Elmarakby
authors.forename: Jessica
authors.initials: J
authors.lastname: Faulkner
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Shabrawey
authors.forename: Mong-Heng
authors.initials: MH
authors.lastname: Wang
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
mesh_terms: D000419:Albuminuria / Q000201:enzymology / Q000517:prevention & control; D000818:Animals; D018932:Chemokine CCL2 / Q000652:urine; D003094:Collagen / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D004851:Epoxide Hydrolases / Q000172:deficiency* / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000652:urine; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism; D009393:Nephritis / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018384:Oxidative Stress; D010766:Phosphorylation; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D008565:Membrane Proteins; C498144:Rela protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; D051996:Transcription Factor RelA; D014665:Vasodilator Agents; C113267:nephrin; D003094:Collagen; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019255:NADPH Oxidases; D051550:I-kappa B Kinase; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse