Metformin attenuates PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway in proximal renal tubular epithelial cells
Abstract
Abstract The harmful effects of PM2.5 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 PM2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM2.5) for 8 weeks. PM2.5 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 PM2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM2.5 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. PM2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM2.5-increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM2.5-induced kidney injury and the protective effect of metformin on PM2.5-induced cellular damage, offering new insights for air pollution-related renal diseases.
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