Dual Soluble Epoxide Hydrolase Inhibitor/PPAR‐γ Agonist Reduces Kidney Injury In Metabolic Syndrome Rat

Abstract

Metabolic syndrome (MetS) is a disease that yields a cluster of symptoms including hypertension, hyperglycemia, hypertriglyceridemia and obesity. Due to the complexity of this syndrome, patients are often prescribed numerous medications, leading to an increased risk of negative drug interactions and higher drug cost. We hypothesize that the development of a dual modulator (a drug that combines two pharmacophores) could treat more than one symptom of MetS and prevent renal injury. Soluble epoxide hydrolase (sEH) inhibitors and PPAR‐γ agonists have therapeutic potential in MetS. We synthesized a novel dual sEH inhibitor‐PPAR‐γ agonist (sEHi/PPAR‐γ), RB394 and investigated its efficacy in a rat model of MetS. Three groups of rats were utilized; Group 1: Wister Kyoto (WKY) + Vehicle (n=6); Group 2: Spontaneously Hypertensive Obese (SHROB) + Vehicle (n=3); Group 3: SHROB + RB394 (10mg/kg/d p.o.; n=5). RB394 or vehicle treatments were administered for 56 days, blood pressure measured, and urine and kidney tissues collected at the end of treatment period. The SHROB rats were hypertensive (187±7 mmHg) compared to WKY rats (137±5 mmHg, P<0.05), and RB394 markedly reduced hypertension in SHROB rats (144±4 mmHg, P<0.05). In order to quantify the amount of kidney injury sustained, we assessed albuminuria and utilized Periodic Acid Schiff stain and Picro Sirius Red stains for histological analysis of renal tubular cast formation, collagen formation and glomerular injury. The SHROB rats developed renal damage with marked albuminuria (243±18 mg/d) compared to WKY (1.0±0.1 mg/d, P<0.05), and RB394 decreased the renal damage by reducing albuminuria (59±11 mg/d, P<0.05). The kidney of SHROB rats had markedly elevated protein cast and collagen, and RB394 reduced the cast and collagen formation by 40–50%. Glomerular injury was also prominent in SHROB rats and RB394 reduced it by 45%. The SHROB rats also had marked renal inflammation with infiltrating immune cells in the kidney, and RB394 reduced it by 20%. Overall, our results demonstrate that a dual sEHi/PPAR‐γ, RB394, prevented renal injury in SHROB MetS rats. These results indicate an exciting opportunity for a new way to more effectively treat patients with MetS.