Sun, P.; Parra, A. C.; Sanches, T. R.; Wikuats, C. F. H.; Butter, L. M.; Claessen, N.; Baelde, H. J.; Schimmel, I.; Van der Wel, N. N.; Janssens, G. J.; Houtkooper, R. H.; Vaz, F. M.; Roelofs, J. J.; Boor, P.; Strauch, M.; Andrade, M. d. F.; Andrade, L.; Florquin, S.; Kers, J.; Romagnolo, A.; Tammaro, A.

Background: Long-term exposure to fine particulate matter (PM2.5) is increasingly recognized as a risk factor for chronic kidney disease (CKD). We previously demonstrated that high-dose PM2.5 exposure prior to ischemia/reperfusion injury (IRI) aggravates acute kidney injury (AKI). Here, we investigated how prolonged, low concentration urban PM2.5 exposure affects kidney repair after AKI. Methods: Six-week-old mice underwent bilateral IRI or sham surgery, followed by six months of exposure to either filtered air or ambient PM2.5 exposure in a unique exposome chamber. Kidneys were analyzed using pathomics, electron and super resolution microscopy, immunohistochemistry, transcriptomics, and LC/MS-based lipidomics and metabolomics. Complementary in vitro hypoxia/reoxygenation and PM2.5 exposure experiments were performed in proximal tubular epithelial cells. Results: Long term PM2.5 exposure had minimal effects in sham operated mice, including no significant changes in body weight or kidney function. Despite preserved kidney function, IRI+PM2.5 mice exhibited reduced weight gain, a marked expansion of the interstitial area, attributable to enhanced fibrosis and inflammatory responses, microvascular rarefaction, and endothelial-to-mesenchymal transition, consistent with maladaptive repair features. Proximal tubules displayed mitochondrial injury, glycolytic reprogramming, lipid accumulation, and a senescent phenotype. Energy Dispersive X ray (EDX) microscopy confirmed PM2.5 derived elements within proximal tubules lysosomes, accompanied by lysosomal stress. Drug screening based on transcriptional signature identified nicotinamide as a compound capable of reversing PM2.5 induced metabolic alterations; in vitro validation confirmed rescue of mitochondrial function in injured proximal tubular epithelial cells. Conclusions: Together, these findings show that chronic post AKI exposure to PM2.5 at levels currently considered safe by regulatory bodies drives maladaptive repair and accelerates CKD progression through mitochondrial dysfunction, lysosomal stress senescence in proximal tubules, due to local PM2.5 element accumulation.