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

Autor: Marianne K. O. Grant, Davis M. Seelig, Wan S. V. Choi, Ibrahim Y. Abdelgawad, Beshay N M Zordoky, Leslie C. Sharkey
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Male
Protein Expression
Gene Expression
Apoptosis
Plant Science
030204 cardiovascular system & hematology
Pharmacology
Kidney
Mice
0302 clinical medicine
Fibrosis
Transforming Growth Factor beta
Gene expression
polycyclic compounds
Medicine and Health Sciences
Morphogenesis
bcl-2-Associated X Protein
Epoxide Hydrolases
Sex Characteristics
Multidisciplinary
Sexual Differentiation
Cell Death
Animal Models
medicine.anatomical_structure
Experimental Organism Systems
Cell Processes
Medicine
Female
Anatomy
medicine.drug
Research Article
Epoxide hydrolase 2
Science
Mouse Models
Antineoplastic Agents
macromolecular substances
Research and Analysis Methods
Nephrotoxicity
03 medical and health sciences
Model Organisms
medicine
Gene Expression and Vector Techniques
Genetics
Animals
Doxorubicin
Molecular Biology Techniques
Molecular Biology
Molecular Biology Assays and Analysis Techniques
Sexual Dimorphism
business.industry
organic chemicals
technology
industry
and agriculture
Biology and Life Sciences
Kidneys
Renal System
Cell Biology
Plant Pathology
medicine.disease
carbohydrates (lipids)
Mice
Inbred C57BL
030104 developmental biology
Animal Studies
business
Transforming growth factor
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 14, Iss 2, p e0212486 (2019)
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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