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Novel Orally Active Epoxyeicosatrienoic Acid (EET) Analogs Attenuate Cisplatin Nephrotoxicity
Author(s) -
Khan Md. Abdul Hye,
Meyer Jessica L,
Walsh Katherine A,
Falck John R,
Jat Jawahar L,
Manthati Vijay L,
Imig John D
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.851.7
Subject(s) - nephrotoxicity , cisplatin , pharmacology , chemistry , kidney , oxidative stress , creatinine , medicine , biochemistry , endocrinology , chemotherapy
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.