Exposure to urban PM2.5 exacerbates renal injury and fibrosis via the lung-kidney axis through IL-6/ADCY3 signaling pathway.

Exposure to fine particulate matter (PM2.5) is associated with renal injury and chronic kidney disease (CKD) progression, yet its mechanisms remain incompletely understood. In this study, we exposed mice to urban PM2.5 at an environmentally relevant dose via the respiratory tract and combined this with renal ischemia-reperfusion injury (IRI) to systematically assess its effects on kidney function and structure. Meanwhile, we investigated the relevant molecular biological mechanisms underlying renal functional and structural damage mediated by the lung-kidney axis following repeated intratracheal PM2.5 exposure. The results indicated that PM2.5 exposure significantly exacerbated renal dysfunction, tubular injury, and fibrosis, accompanied by increased lipid droplet accumulation and upregulation of fibrotic markers, and adenylate cyclase 3 (ADCY3) was identified as a critical target in this pathological process. Mechanistically, PM2.5 induced systemic inflammation and elevated circulating interleukin-6 (IL-6) levels, with alveolar macrophages likely contributing as a key source. Elevated IL-6 subsequently suppressed the function of ADCY3-CREB-PGC1α signaling pathway, leading to impaired fatty acid β-oxidation (FAO), enhanced glycolysis, mitochondrial dysfunction, oxidative stress, and fibrotic progression. Functional experiments further confirmed that blocking IL-6 signaling or overexpressing ADCY3 mitigated renal tubular epithelial cell injury, lipid metabolic dysregulation, and fibrotic responses mediated by PM2.5 exposure both in vivo and in vitro. In conclusion, this study offers a new insight into the intricate molecular mechanisms through which PM2.5 exposure exacerbates renal injury and CKD progression, suggesting that the IL-6/ADCY3 signaling pathway plays a crucial role in renal injury induced by PM2.5 exposure.