A Novel Dual Soluble Epoxide Hydrolase Inhibitor/Cyclooxygenase‐2 Inhibitor Treats Type 2 Diabetic Complications in Obese ZSF1 Rats

Abstract

Diabetes is a highly prevalent chronic disease worldwide that represents a global healthcare burden. A devastating type 2 diabetes complication is diabetic nephropathy. We developed a novel dual modulator, PTUPB that concurrently acts as a soluble epoxide hydrolase (sEH) inhibitor as well as a cyclooxyganse‐2 inhibitor (sEHi/COXi) to combat diabetic nephropathy. The objective for the current investigation is to determine if PTUPB can treat diabetic nephropathy in obese ZSF1 rats. PTUPB was compared to an angiotensin converting enzyme inhibitor that is the current standard of care for diabetic nephropathy. Obese ZSF‐1 rats at 16 weeks of age received PTUPB (10mg/kg/d i.p.) or enalapril (10mg/kg/d, p/o.) for 8 weeks. Type 2 diabetes was assessed in obese ZSF1 rats. Renal injury was determined using several biochemical, histological, and immunohistological techniques. Obese ZSF1 rats were diabetic with fasting blood glucose (19±0.4 vs. 4.8±0.1 mmol/l in lean ZSF1) . Neither PTUPB nor enalapril treated diabetes and did not reduce hyperglycemia or HbA1c in obese ZSF1 rats. Obese ZSF1 rats developed diabetic nephropathy with elevated albuminuria (49±6 vs. 1.3±0.2 mg/mg creatinine in lean ZSF1), tubular cast formation (cortex, 14±1 vs. 1.0±0.1%; medulla, 22.4±2 vs. 0.9±0.2%), renal fibrosis (cortex, 11±1 vs. 4.4±0.3%; medulla, 10±1.2 vs. 4.0±0.8%) and glomerular injury (3.4±0.6 vs. 0.6±0.08 a.u.) compared to lean ZSF1 lean (all P<0.05). PTUPB treated diabetic nephropathy by reducing albuminuria (by 50%), renal tubular cast formation (by 60% in cortex; 70% in medulla), renal fibrosis (by 50% in cortex; 36% in medulla), and glomerular injury (by 55%) compared to vehicle. Enalapril treatment reduced diabetic nephropathy in obese ZSF1 rats like PTUPB and reduced the renal injury parameters by 30 to 50% compared to vehicle. Diabetic renal injury in obese ZSF1 rats was accompanied by inflammation with elevated urinary MCP‐1 levels (29±2 vs. 5±0.6 ng/mg creatinine in lean ZSF1 rat, P<0.05) and renal infiltration of CD‐68 cells (95±10 vs. 16±1.2 cell/mm2, P<0.05). PTUPB or enalapril treated renal inflammation and reduced MCP‐1 excretion (PTUPB reduced by 50% and enalapril reduced by 20%) and renal CD‐68 positive cell infiltration (by 60% and 50%, respectively by PTUPB or enalapril). These findings demonstrate that PTUPB is not anti‐diabetic but markedly treat diabetic nephropathy. We also demonstrate that PTUPB has renal actions comparable to enalapril which is currently the standard of care to treat diabetic nephropathy.Support or Funding InformationNational Institute of Health (NIH) grant (DK103616) and Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee grant to JDI; NIEHS/R01 ES002710 (HAM1400) and NIEHS/Superfund Research Program P42 ES004699 (SUPR?30) to BDHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.