Document Detail

Deletion of soluble epoxide hydrolase gene improves renal endothelial function and reduces renal inflammation and injury in streptozotocin-induced type 1 diabetes.
MedLine Citation:
PMID:  21832210     Owner:  NLM     Status:  MEDLINE    
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.
Ahmed A Elmarakby; Jessica Faulkner; Mohammed Al-Shabrawey; Mong-Heng Wang; Krishna Rao Maddipati; John D Imig
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-08-10
Journal Detail:
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:
Created Date:  2011-11-03     Completed Date:  2011-12-22     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R1307-17     Citation Subset:  IM    
Department of Oral Biology, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
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MeSH Terms
Albuminuria / enzymology,  prevention & control
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
Membrane Proteins / metabolism,  urine
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidase / metabolism
Nephritis / enzymology,  etiology,  genetics,  pathology,  prevention & control*
Oxidative Stress
Thiobarbituric Acid Reactive Substances / metabolism
Time Factors
Transcription Factor RelA / metabolism
Vasodilation* / drug effects
Vasodilator Agents / pharmacology
Grant Support
Reg. No./Substance:
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 Oxygenase-1; EC protein, mouse; EC Oxidase; EC B Kinase; EC 3.3.2.-/Epoxide Hydrolases; EC protein, mouse

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