Independent and synergistic effects of extreme heat and NO2 pollution on diabetic nephropathy in a type II diabetes mouse model

Extreme heat and traffic-related air pollution (TRAP) have been linked to worsening chronic health disorders, however, their combined effects on diabetic nephropathy (DN) are little understood. Type II diabetic mice were exposed to heat (40 °C) and NO₂ (5 ppm) separately for 4 h per day over 6 weeks to investigate the synergistic effects on the progression of DN. We found that exposure to high temperature and NO₂ elevated blood glucose levels and exacerbated histopathological changes. Additionally, there were increased oxidation indicators (ROS, MDA, 8-OHdG) and decreased antioxidant indicators (CAT, SOD, GSH-PX), along with elevated inflammation markers (TNF-α, IL-1β, IL-6). The expressions of transient receptor potential (TRP) ion channels (TRPV1, TRPV4, TRPA1, TRPM2) were also upregulated. Our findings suggest that simultaneous exposure to high temperature and NO₂ impairs metabolic and autophagy pathways. Exposure to both high temperature and NO₂ produces a synergistic effect, leading to more severe damage than exposure to either factor individually. This resulted in increased expression of APOA1, P62, and p-mTOR/mTOR while decreasing the expression of p-AMPKα/AMPKα and LC3-II/I. This disruption promoted the progression of DN. In contrast, capsazepine (CZP) reduced TRP expression, inflammatory markers, oxidative stress, metabolic and autophagy disorders, thereby mitigating renal damage and alleviating the progression of diabetic nephropathy. Our study provides some potential strategies for early prevention and effective reduction of DN.