Role of ferroptosis in cisplatin-induced nephrotoxicity
Ikeda, Yasumasa Tokushima University Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Horinouchi, Yuya Tokushima University
Hirayama, Tasuku Gifu Pharmaceutical University
Nagasawa, Hideko Gifu Pharmaceutical University
Tamaki, Toshiaki Tokushima University|Anan-Medical Center Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Background: Cisplatin is widely used as an antitumor drug for the treatment of solid tumors. However, its use has been limited owing to nephrotoxicity, a major side effect. The mechanism of cisplatin-induced nephrotoxicity (CIN) has long been investigated in order to develop preventive/therapeutic drugs. Ferroptosis is a newly identified form of non-apoptotic regulated cell death induced by iron-mediated lipid peroxidation and is involved in the pathophysiology of various diseases. In this study, we examined the role of ferroptosis in CIN.
Methods: We evaluated the role of ferroptosis in CIN by in vivo experiments in a mouse model.
Results: Cisplatin increased the protein expressions of transferrin receptor-1 and ferritin, and iron content in the kidney of mice. In addition, treatment with cisplatin augmented renal ferrous iron and hydroxyl radical levels with co-localization. Mice administered cisplatin demonstrated kidney injury, with renal dysfunction and increased inflammatory cytokine expression; these changes were ameliorated by Ferrostatin-1 (Fer-1), an inhibitor of ferroptosis. The expression of the ferroptosis markers, COX2 and 4-hydroxynonenal (4-HNE), increased with cisplatin administration, and decreased with the administration of Fer-1. By contrast, cisplatin-induced apoptosis and necroptosis were inhibited by treatment with Fer-1. Moreover, deferoxamine, an iron chelator, also inhibited CIN, with a decrease in the expression of COX-2 and 4-HNE.
Conclusion: Ferroptosis is involved in the pathogenesis of CIN and might be used as a new preventive target for CIN.
Journal of Trace Elements in Medicine and Biology
© 2021. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
|DOI (Published Version)
|URL ( Publisher's Version )
jtemb_67_126798.pdf 1.64 MB