A dual COX‐sEH inhibitor improved glycemic status and reduced kidney injury in Zucker diabetic fatty rat (689.4)

Abstract

Cyclooxygenase (COX) and soluble epoxide hydrolase (sEH) inhibitors have therapeutic potentials. We synthesized a novel dual COX‐sEH inhibitor, PTUPB and investigated its efficacy in type 2 diabetic (T2D) Zucker Diabetic Fatty (ZDF) rats. Male ZDF rats were treated with vehicle or PTUPB (3 mg/d, i.p.) for 56 days. On day 56, 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). ZDF rats also developed hypertension and endothelial dysfunction that were reduced by PTUPB. The ZDF rats demonstrated kidney injury compared to ZDL with elevated albuminurea (4±2 vs 44±4 mg/d), nephriurea (16±4 vs 496±127 µg/d), marked renal fibrosis, cast formation and glomerular injury compared to ZDL rats, and PTUPB treatment reduced this injury by 40‐50%. The ZDF rats also demonstrated increased inflammation and oxidative stress with elevated levels of urinary monocyte chemoattractant protein‐1 excretion (319±75 vs 862±300 ng/d), renal macrophage infiltration (37±4 vs 53±2/mm2) and kidney malondialdehyde/protein ratio (5±1 vs 10±1 µmol/mg) that were decreased with PTUPB treatment by 20‐50%. The data obtained demonstrate the ability of a novel dual COX‐sEH inhibitor to improve glycemic status and reduce kidney injury in T2D.