The mechanism of nickel-induced autophagy and its role in nephrotoxicity

Nickel (Ni), an environmental health hazard, is nephrotoxic to humans, but the exact mechanism is unknown. This study aims to identify whether nephrotoxicity is associated with Autophagy. Here, nickel chloride (NiCl₂) increased Autophagy in TCMK-1 cells. NiCl₂ induces Autophagy through Akt and AMPK/mTOR pathways. Next, oxidative stress was investigated in NiCl₂-induced Autophagy. The findings demonstrated that the antioxidant (NAC) or mitochondrial targeted antioxidant (Mito-TEMPO) attenuated NiCl₂-induced Autophagy, reversed the influence on AMPK-mTOR and Akt pathways. Additionally, our study examined the role of Autophagy in NiCl₂-induced nephrotoxicity. Autophagy inhibition with 3-MA could inhibit cell viability and increase Apoptosis in the TCMK-1 cells, however, Autophagy promotion with rapamycin relieved cytotoxicity and decreased Apoptosis. Additionally, co-treatment with Z-VAD-FMK reduced cytotoxicity, but did not affect Autophagy. Besides, NiCl₂ can increase the level of Mitophagy in vivo and vitro. Mitophagy inhibition could inhibit cell viability and increase Apoptosis in the TCMK-1 cells, whereas, promotion of Mitophagy could increase cell viability and decrease Apoptosis. In summary, above-mentioned results showed that NiCl₂ induces Autophagy in TCMK-1 cells through oxidative stress-dependent AMPK/AKT-mTOR pathway, Autophagy plays a role in reducing NiCl₂-induced renal toxicity, and a major mechanism in autophagy's inhibitory effect on NiCl₂-induced Apoptosis may be Mitophagy.

Apoptosis; Autophagy; Kidney; Mitophagy; Nickel.