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Inhibition of Soluble Epoxide Hydrolase (sEH) Attenuates Cisplatin‐Induced Acute Renal Inflammation
Author(s) -
LIU Yingmei,
Webb Heather,
Kroetz Deanna L
Publication year - 2008
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.22.1_supplement.479.19
Subject(s) - epoxide hydrolase 2 , chemistry , blood urea nitrogen , cisplatin , pharmacology , kidney , inflammation , creatinine , lipocalin , endocrinology , medicine , biochemistry , enzyme , chemotherapy
Epoxyeicosatrienoic acids (EETs) are cytochrome P450‐derived eicosanoids which are metabolized into dihydroxyeicosatrienoic acids by sEH. EETs are found at high levels in the kidney and have anti‐inflammatory effects, leading us to hypothesize that inhibition of sEH would attenuate renal inflammation. Treatment of C57BL/6 mice with cisplatin resulted in a dose‐dependent increase in blood urea nitrogen (BUN), serum creatinine (CREA), and renal levels of neutrophil gelatinase‐associated lipocalin (NGAL). Pretreatment of mice with a novel sEH inhibitor, AR9273, attenuated the increase in cisplatin‐induced BUN and CREA level by 34% (p < 0.05) and 45% (p < 0.01). NGAL expression was barely detectable in cisplatin‐treated mice pretreated with AR9273. The cisplatin‐induced elevation of cyclooxygenase 2 expression in the kidneys was also dramatically reduced in mice treated with AR9273. The effect of cisplatin treatment on BUN and CREA was significantly attenuated in Ephx2 −/− mice compared to Ephx2 +/+ mice. Collectively, these data suggest that inhibition of sEH protects against renal inflammation. This work was supported by UC Discovery Grant bio06‐10576.