Metformin inhibits diabetes induced ferroptosis in renal proximal tubular epithelial cells by up-regulating Nrf2 expression

doi:10.12092/j.issn.1009-2501.2026.01.004

Abstract

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-2 cells. 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.

Key words: metformin, ferroptosis, diabetes, Nrf2

CLC Number:

Ziyu WU, Ting YU, Mouwei ZHENG, Tailin GUO. Metformin inhibits diabetes induced ferroptosis in renal proximal tubular epithelial cells by up-regulating Nrf2 expression[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2026, 31(1): 40-47.

Figures/Tables 5

Fig.1 Protective effect of metformin on renal tubular injury in diabetic mice ($ \overline{x} $±s, n=6) A: Serunm ceatinine of the mice; B: Serunm urea nitrogen of the mice; C: HE staining of renal tissue (×200); D: Renal tubular pathological injury score.

Fig.2 Metformin activates Nrf2 expression in the kidney of diabetic mice ($ \overline{x} $±s, n=6) A: the expression of nuclear factor e2-related factor 2 (Nrf2) protein (immunohistochemistry, ×200); B: the expression of Nrf2 protein (Western blot) in kidney tissue; C: the expression of Nrf2 mRNA in kidney tissue.

Fig.3 Metformin alleviates ferroptosis in the kidney of diabetic mice by inncreasing the expression of GPX4/FTH-1 ($ \overline{x} $±s, n=3) A: Expression of GPX4 and FTH-1 protein in renal tissue (Western blotting); B: The expression of GPX4 mRNA in renal tissue; C: The expression of FTH-1 mRNA in renal tissue; D: The GSH content in kidney tissue; E: The MDA content in kidney tissue; E: The iron content in kidney tissue.

Fig.4 The Nrf2/GPX4/FTH-1 pathway was activated by metformin in HK-2 cells induced high glucose ($ \overline{x} $±s, n=3) A: The expression of Nrf2, GPX4, FTH-1 protein in HK-2 cells were detected by western blotting; B: The expression of Nrf2 mRNA in HK-2 cells; C: The expression of GPX4 mRNA in HK-2 cells; D: The expression of FTH-1 mRNA in HK-2 cells.

Fig.5 The metformin reduced reactive oxygen species production and ferroptosis induced by high glucose in HK-2 cells ($ \overline{x} $±s, n=3) A: Changes of reactive oxygen species in HK-2 cells; B: The GSH content in HK-2 cells; C: The MDA content in HK-2 cells; D: The iron content in HK-2 cells.

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