Salvianolic acid A attenuates arsenic-induced ferroptosis and kidney injury via HIF-2α/DUOX1/GPX4 and iron homeostasis

Arsenic (As) is a prevalent pollutant in the environment and causes a high frequency of kidney disease in areas of high arsenic contamination, but its pathogenic mechanisms have yet to be completely clarified. Ferroptosis is a new form of cell death mainly dependent on lipid peroxidation and iron accumulation. Several reports have suggested that ferroptosis is operative in a spectrum of diseases caused by arsenic exposure, including in the lungs, pancreas, and testis. However, the mechanism and exact role of ferroptosis in arsenic-induced kidney injury is not known. Firstly, by constructing in vivo and in vitro arsenic exposure models, we confirmed the occurrence of ferroptosis based on the identification of the ability of NaASO2 to cause kidney injury. In addition, we found that arsenic exposure could upregulate DUOX1 expression in kidney and HK-2 cells, and after knocking down DUOX1 using siRNA was able to significantly upregulate GPX4 expression and attenuate ferroptosis. Subsequently using bioinformatics, we identified and proved the involvement of HIF-2α in the course of ferroptosis, and further confirmed by dual luciferase assay that HIF-2α promotes DUOX1 transcription to increase its expression. Finally, intervention with the natural ingredient SAA significantly attenuated arsenic-induced ferroptosis and kidney injury. These results showed that arsenic could cause ferroptosis and kidney injury by affecting HIF-2α/DUOX1/GPX4 and iron homeostasis and that SAA was an effective intervention component. This study not only discovered the molecular mechanism of sodium arsenite-induced kidney injury but also explored an active ingredient with intervention potential, providing a scientific basis for the prevention and treatment of sodium arsenite-induced kidney injury.