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  3. Autophagy-mediated ferroptosis involved in nickel-induced nephrotoxicity in the mice

Autophagy-mediated ferroptosis involved in nickel-induced nephrotoxicity in the mice

  • Ecotoxicol Environ Saf. 2023 May 24;259:115049. doi: 10.1016/j.ecoenv.2023.115049.
Qing Yang 1,  Zhicai Zuo 2,  Yuxin Zeng 1,  Yujuan Ouyang 1,  Hengmin Cui 2,  Huidan Deng 2,  Yanqiu Zhu 1,  Junliang Deng 2,  Yi Geng 1,  Ping Ouyang 1,  Weiming Lai 1,  Zongjun Du 3,  Xueqin Ni 1,  Heng Yin 4,  Jing Fang 5,  Hongrui Guo 6
Affiliations

Affiliations

  • 1 College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.
  • 2 College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China.
  • 3 College of Animal Science and Technology, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China.
  • 4 School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China. Electronic address: yinheng0123@163.com.
  • 5 College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. Electronic address: fangjing4109@163.com.
  • 6 College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China; Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu 611130, China. Electronic address: guohongrui@sicau.edu.cn.
PMID: 37235900 DOI: 10.1016/j.ecoenv.2023.115049
Abstract

Nickel, as a widely polluted metal, has been shown nephrotoxicity. Ferroptosis is a new type of cell death driven by iron-dependent lipid peroxidation. Our study found that nickel chloride (NiCl2) induced Ferroptosis in mouse kidney and TCMK-1 cells. The iron content was significantly increased in the kidney and TCMK-1 cells after NiCl2 treatment. Lipid peroxidation and MDA content were significantly increased, and GSH content and T-SOD activity were significantly decreased after exposure to NiCl2. Moreover, NiCl2 increased COX-2 protein levels, decreased SLC7A11 and GPX4 protein levels, and elevated Ptgs2 mRNA levels. Next, the mechanism of Ni-induced Ferroptosis was investigated. The results showed that NiCl2 induced Autophagy in TCMK-1 cells, which promoted Ferroptosis induced by NiCl2. Furthermore, the data of Autophagy activation or inhibition experiment showed that Autophagy facilitated Ferroptosis through the degradation of the iron regulation protein NCOA4 and FTH1. Otherwise, iron chelator DFOM treatment inhibited Ferroptosis induced by NiCl2. Finally, Ferroptosis inhibitor Fer-1 treatment significantly alleviated cytotoxicity induced by NiCl2. To sum up, our above results showed that Ferroptosis is involved in NiCl2-induced nephrotoxicity, and NiCl2 induces autophagy-dependent ferritin degradation, releases iron ions, leads to iron overload, and induces Ferroptosis. This study supplies a new theoretical foundation for the study of nickel and renal toxicity.

Keywords

Autophagy; Ferroptosis; Kidney; Nickel; TCMK-1.

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