Sexually Dimorphic Regulation of Renal Soluble Epoxide Hydrolase by Acute Doxorubicin‐Induced Toxicity

Abstract

BackgroundDoxorubicin (DOX) is one of the most effective chemotherapeutic agents. Nevertheless, clinical utility is limited due to multiple organ toxicities. Nephrotoxicity has been reported in rodent models and to a lesser degree in cancer patients. Notably, female rodents are protected against DOX‐induced nephrotoxicity relative to males; however, the mechanism has not been elucidated. Soluble epoxide hydrolase (sEH) metabolizes renoprotective epoxyeicosatrienoic acids (EETs), diminishing their biological activity and potentiating kidney injury. Importantly, renal sEH expression has been shown to exhibit sexual dimorphism. Moreover, inhibition of sEH in male mice and rats protected against DOX‐induced nephrotoxicity. Herein, we have determined the effect of acute DOX administration on renal expression of sEH in male and female mice.MethodsAcute DOX toxicity was induced by a single intra‐peritoneal injection of 20 mg/kg DOX in male and female adult C57Bl/6 mice. Mice were euthanized 1, 3, and 6 days following DOX or saline injection. Kidneys and testes were harvested, weighed, and snap frozen in liquid nitrogen. DOX‐induced nephrotoxicity was assessed by histopathology. Renal sEH protein expression was measured by western blot analysis. In another cohort of naive mice, which did not receive DOX, renal sEH protein expression was measured in adult gonadectomized male and female mice as compared to sham‐operated animals.ResultsThe DOX‐treated male mice demonstrated inflammatory and degenerative renal pathology and increased deposition of collagen in both the interstitial space and surrounding glomeruli. No such pathology was identified in the male control mice or either group of female mice. Constitutive expression of renal sEH in the females was significantly lower than that in the males. There was a marked inhibition of renal sEH protein expression in DOX‐treated male, but not female, mice 3 and 6 days following DOX administration. This was accompanied by a significant decrease in testes weight indicating DOX‐induced gonadotoxicity. Interestingly, renal sEH protein expression was also significantly lower in castrated naive mice compared to sham control. Conversely, ovariectomy had no significant effect on renal sEH expression in female miceConclusionsOur findings confirmed marked sexual dimorphism of DOX‐induced nephrotoxicity which may have been mediated by the lower constitutive expression of renal sEH in female mice. DOXinduced inhibition of renal sEH may have been secondary to DOX‐induced gonadotoxicity in male mice and suggests a negative feedback protective mechanism.Support or Funding InformationResearch was funded by the Masonic Cancer Center and administered by the University of Minnesota Women's Health Research Program (BNZ), and by a research grant from the Rally Foundation for Childhood Cancer Research (BNZ).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.