Polystyrene microplastics induce nephrotoxicity through DDIT4-mediated autophagy and apoptosis
Yujiao Wang, Anxiu Zhang, Ting Liang, Long Chen, Shuqi Feng, Zhuoyuan Zhao, Ziye Jing, Jieping Lv, Jun Xie, Bing‐Rui Zhou
Abstract
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. • Polystyrene microplastics disrupt renal development in kidney organoid models. • RNA sequencing reveals PS-MP-induced DNA damage and hypoxia in nephron progenitor cells. • PS-MP exposure downregulates mTOR signaling via DDIT4, promoting autophagy. • DDIT4 activation also triggers apoptosis, exacerbating nephrotoxicity. • Silencing DDIT4 mitigates PS-MP-induced autophagy and apoptosis in NPCs.