Faculty Collaboration Database

Deletion of soluble epoxide hydrolase gene improves renal endothelial function and reduces renal inflammation and injury in streptozotocin-induced type 1 diabetes. Am J Physiol Regul Integr Comp Physiol 2011 Nov;301(5):R1307-17

Date

08/13/2011

Pubmed ID

21832210

Pubmed Central ID

PMC3213948

DOI

10.1152/ajpregu.00759.2010

Scopus ID

2-s2.0-80155165329 (requires institutional sign-in at Scopus site)   71 Citations

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.

Author List

Elmarakby AA, Faulkner J, Al-Shabrawey M, Wang MH, Maddipati KR, Imig JD

MESH terms used to index this publication - Major topics in bold

Albuminuria
Animals
Chemokine CCL2
Collagen
Diabetes Mellitus, Experimental
Diabetes Mellitus, Type 1
Diabetic Nephropathies
Dose-Response Relationship, Drug
Endothelium, Vascular
Epoxide Hydrolases
Heme Oxygenase-1
I-kappa B Kinase
Inflammation Mediators
Kidney
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
NADPH Oxidases
Nephritis
Oxidative Stress
Phosphorylation
Thiobarbituric Acid Reactive Substances
Time Factors
Transcription Factor RelA
Vasodilation
Vasodilator Agents