Polystyrene Nanoplastics Chronic Exposure Aggravates Diabetic Kidney Injury in mice: role of mtROS/Sirt1 axis mediated renal tubular senescence

Abstract Previous studies have suggested that polystyrene nanoplastics (PS-NPs) preferentially accumulate in the kidneys, posing a new threat to people with diabetic nephropathy. However, the adverse effect of chronic exposure of PS-NPs on diabetic kidney and underlying mechanisms remain largely unknown. Diabetic mice were orally administered PS-NPs (80 nm) at different doses (1, 10, and 50 mg/kg/day) for 60 days. PS-NPs was found mainly accumulated in the renal tubules rather than the glomeruli and caused tubular-specific damage as indicated by both pathological changes and increased levels of KIM-1/creatinine and NAG/creatinine in the urine. Mechanistically, the RNA-seq analysis of the kidney tissues of diabetic mice treated with PS-NPs revealed significant changes in mitochondrial-related genes.Co-localization of PS-NPs and mitochondria was detected in PS-NPs treated HK-2 cells, along with an increase in mtROS levels and a decrease in Sirt1 expression based on the experimental results from diabetic mice and HK-2 cells. Using the endocytosis inhibitor EIPA to inhibit the uptake of PS-NPs by HK-2 cells significantly reduced the mtROS levels within the cells. Furthermore, renal tubular senescence manifested by an increase in SA-β-galactosidase activity was further detected in both PS-NPs treated mice and HK-2 cells and that could be partially attenuated by the ROS inhibitor NAC.Overall, our study shows that PS-NPs mainly accumulate in the renal tubules rather than the glomeruli and can mediate the senescence of HK-2 cells by regulating the mtROS/Sirt1 axis.