Change in soluble epoxide hydrolase (sEH) during cisplatin-induced acute renal failure in mice

• Published in: Journal of toxicological sciences 2015/08/01, Vol.40(4), pp.451-457
• Main Authors: Hashimoto, Terumasa, Fang, Yang-Il, Ohata, Hisayuki, Honda, Kazuo
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - toxicity; Cisplatin; Cisplatin - toxicity; Down-Regulation - drug effects; Epoxide Hydrolases - genetics; Epoxide Hydrolases - metabolism; Epoxyeicosatrienoic acid; Feedback, Physiological; Gene Expression - drug effects; Gene Expression Regulation, Enzymologic - drug effects; Kidney - drug effects; Kidney - enzymology; Male; Mice, Inbred Strains; Nephrotoxicity; Oxidative Stress - drug effects; Oxidative Stress - genetics; Soluble epoxide hydrolase; Thiobarbituric Acid Reactive Substances - metabolism; Thiobarbituric Acid Reactive Substances - pharmacology
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.40.451

Cisplatin is one of the most effective chemotherapeutic agents against various types of cancers; however, it is also associated with nephrotoxicity. Recently, it was reported that inflammatory mechanisms play a key role in the development of nephrotoxicity. Epoxyeicosatrienoic acids (EETs) have an anti-inflammatory effect and are metabolized by soluble epoxide hydrolase (sEH: encoded by EPHX2 gene). Here, we determined the change in sEH activity and EPHX2 expression in renal tissue associated with the development of cisplatin-induced nephrotoxicity. Cisplatin administration decreased hydrolase activity accompanied by down-regulation of sEH and EPHX2 expression. The down-regulation occurred prior to the elevation of blood urea nitrogen (BUN) and tumor necrosis factor-α (TNF-α) gene expression or at treatment with low dose cisplatin. In addition, a negative correlation was found between EPHX2 expression and renal thiobarbituric acid reactive substance (TBARS), and edaravone, a radical scavenger, administration did not down-regulate expression of this gene. The results of this study suggest that cisplatin decreased sEH activity through the down-regulation of sEH and EPHX2 expression, and this down-regulation was involved in a negative feedback loop to protect renal tissue from further damage. Thus, sEH is a potential therapeutic target of cisplatin-induced nephrotoxicity.