Polystyrene Microplastics Activate Noncanonical TGF-β Signaling and Metabolomic Reprogramming to Promote Epithelial-Mesenchymal Transition and Fibrosis in the Kidney

Polystyrene microplastics (PS-MPs) have been detected in human kidneys, raising concerns about their potential health risks. In this study, we investigated the effects of 1 μm PS-MPs in BALB/c mice and NRK-52E cells. After 28 days of exposure to PS-MPs (0.1, 1, and 10 mg/kg), we observed decreased body weight and elevated levels of serum creatinine and other kidney injury markers. PS-MPs accumulated in the kidney, as confirmed by MicroRaman spectroscopy, and caused significant histopathological changes and an increase in mesenchymal markers (α-SMA, fibronectin, collagen IV, and vimentin) while reducing the epithelial marker, E-Cadherin. Further mechanistic studies revealed the activation of the noncanonical TGFβ pathway involving P38MAPK, Akt, STAT3, STAT5, and NF-κB, which led to epithelial-mesenchymal transition (EMT) and the early onset of kidney fibrosis. Moreover, NMR-based metabolomics indicated changes in metabolites involved in energy and amino-acid metabolism, including decreased levels of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine), phenylalanine, and increased glutamine levels. This altered metabolomic pathways, including the biosynthesis of phenylalanine, tyrosine, and tryptophan, as well as phenylalanine metabolism, which have been previously associated with chronic kidney disease. Overall, this study indicates that exposure to PS-MPs may jeopardize renal health by altering metabolic pathways and signaling related to EMT and kidney fibrosis.