| Deletion of soluble epoxide hydrolase gene improves renal endothelial function and reduces renal inflammation and injury in streptozotocin-induced type 1 diabetes. | |
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MedLine Citation:
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PMID: 21832210 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Ahmed A Elmarakby; Jessica Faulkner; Mohammed Al-Shabrawey; Mong-Heng Wang; Krishna Rao Maddipati; John D Imig |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-08-10 |
Journal Detail:
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Title: American journal of physiology. Regulatory, integrative and comparative physiology Volume: 301 ISSN: 1522-1490 ISO Abbreviation: Am. J. Physiol. Regul. Integr. Comp. Physiol. Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-03 Completed Date: 2011-12-22 Revised Date: 2012-04-30 |
Medline Journal Info:
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Nlm Unique ID: 100901230 Medline TA: Am J Physiol Regul Integr Comp Physiol Country: United States |
Other Details:
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Languages: eng Pagination: R1307-17 Citation Subset: IM |
Affiliation:
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Department of Oral Biology, Georgia Health Sciences University, Augusta, Georgia 30912, USA. aelmarakby@georgiahealth.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Albuminuria
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enzymology,
prevention & control Animals Chemokine CCL2 / urine Collagen / urine Diabetes Mellitus, Experimental / complications*, enzymology, genetics, pathology, physiopathology Diabetes Mellitus, Type 1 / complications*, enzymology, genetics, pathology, physiopathology Diabetic Nephropathies / enzymology, etiology, genetics, pathology, physiopathology, prevention & control* Dose-Response Relationship, Drug Endothelium, Vascular / drug effects, physiopathology* Epoxide Hydrolases / deficiency*, genetics Heme Oxygenase-1 / metabolism I-kappa B Kinase / metabolism Inflammation Mediators / metabolism Kidney / blood supply, drug effects, enzymology*, pathology Male Membrane Proteins / metabolism, urine Mice Mice, Inbred C57BL Mice, Knockout NADPH Oxidase / metabolism Nephritis / enzymology, etiology, genetics, pathology, prevention & control* Oxidative Stress Phosphorylation Thiobarbituric Acid Reactive Substances / metabolism Time Factors Transcription Factor RelA / metabolism Vasodilation* / drug effects Vasodilator Agents / pharmacology |
| Grant Support | |
ID/Acronym/Agency:
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HL-59699/HL/NHLBI NIH HHS; R01 HL059699/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Ccl2 protein, mouse; 0/Chemokine CCL2; 0/Inflammation Mediators; 0/Membrane Proteins; 0/Rela protein, mouse; 0/Thiobarbituric Acid Reactive Substances; 0/Transcription Factor RelA; 0/Vasodilator Agents; 0/nephrin; 9007-34-5/Collagen; EC 1.14.99.3/Heme Oxygenase-1; EC 1.14.99.3/Hmox1 protein, mouse; EC 1.6.3.1/NADPH Oxidase; EC 2.7.11.10/I-kappa B Kinase; EC 3.3.2.-/Epoxide Hydrolases; EC 3.3.2.3/Ephx2 protein, mouse |
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