GPX4 utilization by selenium is required to alleviate cadmium‐induced ferroptosis and pyroptosis in sheep kidney

Abstract Cadmium (Cd), a persistent and harmful heavy metal in the environment, can accumulate in the kidneys and cause nephrotoxicity. Selenium (Se) is a beneficial natural element that alleviates the toxicity of Cd. To ascertain the relationship between the protective mechanism of Se against Cd nephrotoxicity and ferroptosis and pyroptosis, we randomly divided 48 sheep into four groups and treated them with Cd chloride and/or sodium selenite for 50 days. The data confirmed that Cd apparently resulted in impaired kidney histology and function, depletion of GSH and nicotinamide adenine dinucleotide phosphate contents and CAT and SOD activities, elevation of MDA level, as well as the reduction in selenoprotein mRNA (GPX1, GPX4, TXNRD1, SELP) levels and GPX4 protein level and immunofluorescence intensity. Meanwhile, Cd induced ferroptosis by causing iron overload, up‐regulating PTGS2, NCOA4, TFR1, and LC3B mRNA levels and PTGS2 and LC3B‐II/LC3B‐I protein levels, reducing SLC7A11 and FTH1 mRNA and protein levels, and enhancing the immunofluorescence co‐localization of FTH1/LC3B. Moreover, it was also found that Cd triggered pyroptosis, which was evidenced by the increase of NLRP3 immunohistochemical positive signal, GSDMD‐N immunofluorescence intensity, IL‐1β and IL‐18 release and the levels of pyroptosis‐related mRNA (NLRP3, ASC, Caspase‐1, GSDMD, IL‐1β and IL‐18) and proteins (NLRP3, Caspase‐1p20, GSDMD‐N, IL‐1β and IL‐18). Notably, Se increased the expression level of GPX4 and the transcription factors TFAP2c and SP1, and ameliorated Cd‐induced changes in aforementioned factors. In conclusion, GPX4 utilization by Se might be required to alleviate Cd‐induced ferroptosis and pyroptosis in sheep kidney.