title: A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat.
abstract: Cyclooxygenase (COX) and soluble epoxide hydrolase (sEH) inhibitors have therapeutic potential. The present study investigated efficacy of a novel dual acting COX-2/sEH inhibitor, PTUPB in type 2 diabetic Zucker Diabetic Fatty (ZDF) rats. Male ZDF rats were treated with vehicle or PTUPB (10mg/kg/d, i.p.) for 8 weeks. At the end of the 8-week experimental period, ZDF rats were diabetic (fasting blood glucose, 287±45mg/dL) compared to Zucker Diabetic Lean rats (ZDL, 99±6mg/dL), and PTUPB treatment improved glycemic status in ZDF rats (146±6mg/dL). Kidney injury was evident in ZDF compared to ZDL rats with elevated albuminurea (44±4 vs 4±2mg/d) and nephrinurea (496±127 vs 16±4μg/d). Marked renal fibrosis, tubular cast formation and glomerular injury were also present in ZDF compared to ZDL rats. In ZDF rats, PTUPB treatment reduced kidney injury parameters by 30-80% compared to vehicle. The ZDF rats also demonstrated increased inflammation and oxidative stress with elevated levels of urinary monocyte chemoattractant protein-1 excretion (862±300 vs 319±75ng/d), renal macrophage infiltration (53±2 vs 37±4/mm(2)) and kidney malondialdehyde/protein ratio (10±1 vs 5±1μmol/mg). PTUPB treatment decreased these inflammatory and oxidative stress markers in the kidney of ZDF rats by 25-57%. These data demonstrate protective actions of a novel dual acting COX-2/sEH inhibitor on the metabolic abnormalities and kidney function in ZDF rat model of type 2 diabetes.
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Md Abdul
authors.initials: MA
authors.lastname: Hye Khan
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
authors.affiliation: Department of Entomology and Nematology and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Pharmacology & Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: jdimig@mcw.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007668:Kidney / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D008297:Male; D055442:Metabolome / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D004851:Epoxide Hydrolases; D013449:Sulfonamides; D000096926:Benzenesulfonamides
keywords: Diabetes; Diabetic nephropathy; Eicosanoid; Inflammation; Oxidative stress