Polystyrene microplastics induce nephrotoxicity through DDIT4-mediated autophagy and apoptosis

Microplastics (MPs), plastic particles smaller than 5 mm, have garnered increasing attention due to their pervasive presence in the environment and potential health risks. While their accumulation in various organs, including the liver, kidneys, and intestines, is well-documented, the specific mechanisms they affect kidney development remain unclear. This study investigated the nephrotoxic effects of 1 μm polystyrene microplastics (PS-MPs) using a 3D kidney organoid model derived from human pluripotent stem cells, focusing on the molecular pathways involved. Kidney organoids were exposed to PS-MPs at concentrations ranging from 1.25 to 10 μg/mL for 24 h. The results demonstrated significant reductions in organoid size and nephron-specific markers, including impaired formation of proximal and distal tubules. Furthermore, enhanced autophagy and apoptosis were observed in nephron progenitor cells (NPCs), as evidenced by a 3.5-fold increase in LC3-II expression and a 1.5-fold increase in cleaved caspase-3 levels. Transcriptomic analysis identified DNA damage-inducible transcript 4 (DDIT4) as a key mediator, linking PS-MP exposure to the inhibition of mTOR signaling. Notably, silencing DDIT4 alleviated PS-MP-induced autophagy and apoptosis, highlighting its crucial role in microplastic-induced nephrotoxicity. These findings provide novel insights into the molecular pathways underlying microplastic-induced toxicity and emphasize the need for further research to explore the developmental impacts and long-term health consequences of microplastic exposure.