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

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 (NiCl) induced ferroptosis in mouse kidney and TCMK-1 cells. The iron content was significantly increased in the kidney and TCMK-1 cells after NiCl treatment. Lipid peroxidation and MDA content were significantly increased, and GSH content and T-SOD activity were significantly decreased after exposure to NiCl. Moreover, NiCl 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 NiCl induced autophagy in TCMK-1 cells, which promoted ferroptosis induced by NiCl. 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 NiCl. Finally, ferroptosis inhibitor Fer-1 treatment significantly alleviated cytotoxicity induced by NiCl. To sum up, our above results showed that ferroptosis is involved in NiCl-induced nephrotoxicity, and NiCl 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.