Novel Orally Active Epoxyeicosatrienoic Acid (Eet) Analogs Attenuate Cisplatin Nephrotoxicity

Nephrotoxicity severely limits the use of the anti‐cancer drug cisplatin. Oxidative stress and inflammation contribute to cisplatin‐nephrotoxicity. Recently, EET analogs have been developed and demonstrate kidney protection in hypertension. Robust orally active EET analogs (EET‐A & EET‐B) were developed by modifying the carboxylate, olefins, and epoxide. We hypothesized that EET analogs would decrease cisplatin‐nephrotoxicity. Cisplatin was injected (7mg/kg) in rats pretreated with EET analogs (10mg/kg/d) for 7 days. On day 5 following cisplatin injection, urine, plasma and kidney were collected. Cisplatin‐nephrotoxicity is manifested by a 3–5‐fold increase in BUN, plasma creatinine (PCr), urinary N‐acetyl‐(D)‐glucosaminidase activity (NAG), and renal tubular cast formation. EET analogs attenuated cisplatin‐induced increases in BUN (EET‐A: 108±30 & EET‐B: 120±33 vs Veh: 241±51 mg/dL), PCr (2.0±0.2 & 1.4±0.2 vs. 3.1±0.2 mg/dL), and NAG (0.5±0.1 & 0.6±0.2 vs 3.0±0.6 U/d). EET analogs also reduced renal cast by 50%. EET analogs reduced cisplatin‐induced kidney TBARS (EET‐A: 7±1; EET‐B: 8±1 vs Veh. 16±2 μmol/g). Cisplatin‐nephrotoxicity was accompanied by elevated renal inflammation and apoptosis and EET analogs reduced their expression. Collectively, these data demonstrate that orally active EET analogs protect from cisplatin‐nephrotoxicity by reducing oxidative stress and inflammation.