Source Data file.xlsx

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. Leptin receptor-deficient db/db mice were exposed to heat (40 °C) and NO₂ (5 ppm) separately for 4 hours per day over 6 weeks to investigate the synergistic effects on the progression of DN. We found that co-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 indicate that co-exposure to high temperature and NO₂ disrupted the metabolic and autophagy pathway, increasing the expression of APOA1 and mTOR while decreasing AMPK and LC3-I/II expression. 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. We identify environmental and climatic risk factors associated with DN that will influence the future survival conditions of people with diabetes and highlight their importance in management strategies.