Cadmium promotes ferroptosis in renal tubular epithelial cells by inducing autophagy

Abstract

Objective To investigate the role of ferritinophagy-mediated ferroptosis in renal tubular epithelial cytotoxicity induced by cadmium (Cd) exposure. Methods HK-2 cells were used to construct Cd exposed cell model, and the effects of Cd on ferroptosis, autophagy, ferritinophagy and cytotoxicity were observed. Meanwhile, the effects of inhibition of ferroptosis, autophagy and ferritinophagy on Cd cytotoxicity were evaluated. Results Cd induced ferroptosis in renal tubular epithelial cells in a dose-dependent manner, and the level of acyl-CoA synthetase long chain family member 4 (ACSL4) was increased and that of glutathione peroxidase 4 (GPX4) was decreased. Treatment of lipid peroxidation inhibitor ferrastatin-1 (Fer-1) and iron chelating agent deferroamine (DFO) attenuated Cd-induced death in renal tubular epithelial cells. Cd induced renal tubular epithelial cell autophagy, increased the number of autophagosomes, and enhanced the expression of autophagy marker LC3B-Ⅱ. Inhibition of autophagy alleviated Cd-induced ferroptosis in renal tubular epithelial cells. In addition, Cd induced ferritinophagy in renal tubular epithelial cells, and the expression of ferritinophagy marker nuclear receptor coactivator 4 (NCOA4) was elevated, while the expression of ferritin heavy chain 1(FTH), substrate of ferritinophagy, was decreased. NCOA4 knockdown inhibited Cd-induced ferritin degradation and cell death. Conclusion Ferritinophagy-mediated ferroptosis is involved in Cd-induced renal tubular epithelial cell death.

Keywords

• cadmium chloride
• nephrotoxicity
• ferroptosis
• ferrotinophagy
• autophagy