Metformin inhibits diabetes induced ferroptosis in renal proximal tubular epithelial cells by up-regulating NRF2 expression

【ABSTRACT】 AIM: To investigate the mechanism of metformin in inhibiting ferroptosis of diabetic renal tubular epithelial cells by promoting the expression of Nrf2. METHODS: 8-week-old DBA2/J male mice were divided into normal control group, Met group, DM group and DM+Met group. HK-2 cells were divided into four groups: normal glucose group, Met group, high glucose group (30 mmmol/L) and HG + Met group. The changes of Scr, BUN ,ROS, the protein and mRNA expression levels of Nrf2, GPX4 and FTH-1 were measured in the kidney of mice or HK-2 cells. The contents of MDA, Fe2+ and GSH were also detected in renal tissues or the HK-2cells. RESULTS: Compared with the DM group, the levels of BUN, Scr and the score of renal pathological injury scores were significantly reduced and the protein expressions of Nrf2, GPX4 and FTH-1 were significantly increased in the kidney tissue of diabetes mice treated with metformin(all p＜0.05) . Compared with the HG group, the expression levels of Nrf2, GPX4, FTH-1 protein and mRNA were significantly promoted, the GSH content was increased and intracellular ROS, MDA, and Fe2+content were decreased in high glucose-induced HK-2 cells treated with metformin ( all p＜0.05).CONCLUSION:Metformin can suppress ferroptosis induced by high glucose and alleviate diabetic tubulopathy. The mechanism may be through up-regulating the expression of Nrf2 in renal tubular epithelial cells.