Metformin attenuates PM_2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway in proximal renal tubular epithelial cells

Abstract

The harmful effects of PM_2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM_2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM_2.5) for 8 weeks. PM_2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM_2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM_2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM_2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM_2.5-increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM_2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM_2.5-induced kidney injury and the protective effect of metformin on PM_2.5-induced cellular damage, offering new insights for air pollution-related renal diseases.

Keywords:

• PM_2.5
• AhR/CYP1A1
• oxidative stress
• metformin
• proximal renal tubular epithelial cells

CRediT authorship contribution statement

Jing Cui: Data curation, Formal analysis, Methodology, Validation, Writing – original draft. Weilin Chen: Investigation, Validation. Dongdong Zhang: Data curation, Formal analysis. Mengqiu Lu: Data curation. Zhijun Huang: Methodology, Project administration, Supervision, Writing – review & editing. Bin Yi: Methodology, Project administration, Supervision, Writing – review & editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data will be made available on request.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (No.82173905, No.82070759) and Provincial Natural Science Foundation of Hunan (No.2024JJ5519).