Sexual dimorphism of acute doxorubicin-induced nephrotoxicity in C57Bl/6 mice

Marianne K.O. Grant, Davis Seelig, Leslie C Sharkey, Wan S.V. Choi, Ibrahim Y. Abdelgawad, Beshay Zordoky

Research output: Contribution to journalArticle

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent that has been reported to cause nephrotoxicity in rodent models and to a lesser degree in cancer patients. Female rodents have been shown to be protected against several features of DOX-induced nephrotoxicity. Nevertheless, the underlying mechanisms of this sexual dimorphism are not fully elucidated. Therefore, in the current study, we investigated the sex and time-dependent changes in pathological lesions as well as apoptotic and fibrotic markers in response to acute DOX-induced nephrotoxicity. We also determined the effect of acute DOX treatment on the renal expression of the sexually dimorphic enzyme, soluble epoxide hydrolase (sEH), since inhibition of sEH has been shown to protect against DOX-induced nephrotoxicity. Acute DOX-induced nephrotoxicity was induced by a single intra-peritoneal injection of 20 mg/kg DOX to male and female adult C57Bl/6 mice. The kidneys were isolated 1, 3 and 6 days after DOX administration. Histopathology assessment, gene expression of the apoptotic marker, BAX, protein expression of the fibrotic marker, transforming growth factor-β (TGF-β), and gene and protein expression of sEH were assessed. DOX administration caused more severe pathological lesions as well as higher induction of the apoptotic and fibrotic markers in kidneys of male than in female mice. Intriguingly, DOX inhibited sEH protein expression in kidneys of male mice sacrificed at 3 and 6 days following administration, suggesting that induction of sEH is not necessary for acute DOX-induced nephrotoxicity. However, DOX-induced inhibition of renal sEH in male mice may protect the kidney from further DOX-induced injury in a negative feedback mechanism. We also observed lower constitutive expressions of TGF-β and sEH in the kidney of female mice which may contribute, at least in part, to sexual dimorphism of DOX-induced nephrotoxicity.

Original languageEnglish (US)
Article numbere0212486
JournalPloS one
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2019

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nephrotoxicity
doxorubicin
Sex Characteristics
sexual dimorphism
Doxorubicin
epoxide hydrolase
Epoxide Hydrolases
mice
kidneys
Kidney
transforming growth factors
protein synthesis
Transforming Growth Factors
lesions (animal)
Rodentia
rodents
Gene Expression
gene expression
Proteins
intraperitoneal injection

PubMed: MeSH publication types

  • Journal Article

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Sexual dimorphism of acute doxorubicin-induced nephrotoxicity in C57Bl/6 mice. / Grant, Marianne K.O.; Seelig, Davis; Sharkey, Leslie C; Choi, Wan S.V.; Abdelgawad, Ibrahim Y.; Zordoky, Beshay.

In: PloS one, Vol. 14, No. 2, e0212486, 01.02.2019.

Research output: Contribution to journalArticle

Grant, Marianne K.O. ; Seelig, Davis ; Sharkey, Leslie C ; Choi, Wan S.V. ; Abdelgawad, Ibrahim Y. ; Zordoky, Beshay. / Sexual dimorphism of acute doxorubicin-induced nephrotoxicity in C57Bl/6 mice. In: PloS one. 2019 ; Vol. 14, No. 2.
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abstract = "Doxorubicin (DOX) is a chemotherapeutic agent that has been reported to cause nephrotoxicity in rodent models and to a lesser degree in cancer patients. Female rodents have been shown to be protected against several features of DOX-induced nephrotoxicity. Nevertheless, the underlying mechanisms of this sexual dimorphism are not fully elucidated. Therefore, in the current study, we investigated the sex and time-dependent changes in pathological lesions as well as apoptotic and fibrotic markers in response to acute DOX-induced nephrotoxicity. We also determined the effect of acute DOX treatment on the renal expression of the sexually dimorphic enzyme, soluble epoxide hydrolase (sEH), since inhibition of sEH has been shown to protect against DOX-induced nephrotoxicity. Acute DOX-induced nephrotoxicity was induced by a single intra-peritoneal injection of 20 mg/kg DOX to male and female adult C57Bl/6 mice. The kidneys were isolated 1, 3 and 6 days after DOX administration. Histopathology assessment, gene expression of the apoptotic marker, BAX, protein expression of the fibrotic marker, transforming growth factor-β (TGF-β), and gene and protein expression of sEH were assessed. DOX administration caused more severe pathological lesions as well as higher induction of the apoptotic and fibrotic markers in kidneys of male than in female mice. Intriguingly, DOX inhibited sEH protein expression in kidneys of male mice sacrificed at 3 and 6 days following administration, suggesting that induction of sEH is not necessary for acute DOX-induced nephrotoxicity. However, DOX-induced inhibition of renal sEH in male mice may protect the kidney from further DOX-induced injury in a negative feedback mechanism. We also observed lower constitutive expressions of TGF-β and sEH in the kidney of female mice which may contribute, at least in part, to sexual dimorphism of DOX-induced nephrotoxicity.",
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