A dual COX-2/sEH inhibitor improves the metabolic profile and reduces kidney injury in Zucker diabetic fatty rat

- We investigated effects of a novel dual acting molecule that concurrently inhibits two arachidonic acid metabolizing enzymes (cyclooxygenase-2 and soluble epoxide hydrolase) on type 2 diabetes and diabetic nephropathy.
- The dual acting molecule, PTUPB was anti-diabetic and reduced kidney injury in the Zucker type 2 diabetic fatty rat.
- Our findings demonstrate the potential for a novel dual acting molecule, PTUPB to be developed further as a therapeutic for type 2 diabetes and diabetic nephropathy.

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 (10 mg/kg/d, i.p.) for 8 weeks. At the end of the 8-week experimental period, ZDF rats were diabetic (fasting blood glucose, 287 ± 45 mg/dL) compared to Zucker Diabetic Lean rats (ZDL, 99 ± 6 mg/dL), and PTUPB treatment improved glycemic status in ZDF rats (146 ± 6 mg/dL). Kidney injury was evident in ZDF compared to ZDL rats with elevated albuminurea (44 ± 4 vs 4 ± 2 mg/d) and nephrinurea (496 ± 127 vs 16 ± 4 μg/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 ± 75 ng/d), renal macrophage infiltration (53 ± 2 vs 37 ± 4/mm2) and kidney malondialdehyde/protein ratio (10 ± 1 vs 5 ± 1 μmol/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.