Role of ferroptosis in cisplatin-induced nephrotoxicity
堀ノ内, 裕也 Tokushima University
Hirayama, Tasuku Gifu Pharmaceutical University
永澤, 秀子 Gifu Pharmaceutical University
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
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