Role of ferroptosis in cisplatin-induced acute nephrotoxicity in mice

Yasumasa Ikeda, Hirofumi Hamano, Yuya Horinouchi, Licht Miyamoto, Tasuku Hirayama, Hideko Nagasawa, Toshiaki Tamaki, Koichiro Tsuchiya

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number126798
JournalJournal of Trace Elements in Medicine and Biology
Volume67
DOIs
Publication statusPublished - Sep 2021
Externally publishedYes

Keywords

  • Cisplatin
  • Ferroptosis
  • Ferrous iron
  • Lipid peroxidation
  • Nephrotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Inorganic Chemistry

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