Lin Chien-Hung, Liu Wen-Sheng, Wan Chuan, Wang Hsin-Hui
Division of Pediatric Immunology and Nephrology, Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; College of Science and Engineering, Fu Jen Catholic University, New Taipei, Taiwan.
School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; College of Science and Engineering, Fu Jen Catholic University, New Taipei, Taiwan; Division of Nephrology, Department of Medicine, Taipei City Hospital Zhongxing Branch, Taipei, Taiwan; Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; Department of Special Education, University of Taipei, Taipei, Taiwan.
Toxicol Appl Pharmacol. 2025 Feb;495:117184. doi: 10.1016/j.taap.2024.117184. Epub 2024 Dec 2.
Increasing evidence links exposure to fine particulate matter (PM2.5) with an elevated risk of kidney disease. In this study, we investigated the effect of PM2.5 exposure on human proximal tubular epithelial (HK-2) cells and found that it elevated ferroptotic stress markers, including increased iron, reactive oxygen species (ROS), and malondialdehyde (MDA), along with reducing glutathione (GSH) levels. PM2.5 promotes the epithelial-to-mesenchymal transition (EMT) in these cells, which is associated with the loss of epithelial morphology, lowered expression of E-cadherin, and elevated expression of α-smooth muscle actin (α-SMA). Notably, a reduction in PM2.5-induced EMT characteristics was observed using either a ferroptosis-specific inhibitor (Fer-1) or a mitochondrial ROS scavenger (Mito-Tempo). Moreover, Fer-1 effectively counteracted ferroptotic stress and restored glutathione peroxidase 4 (GPX4) expression in PM2.5-exposed cells, which may explain its efficacy in inhibiting EMT induced by PM2.5. In contrast, GPX4 knockdown exacerbated EMT features in PM2.5-treated cells. Further studies showed that GPX4 overexpression alleviated EMT markers in mouse tubular cells following PM2.5 exposure, indicating the role of GPX4 in reducing ferroptotic stress and may prevent tubular injury caused by PM2.5 exposure. Our study highlights that PM2.5 may induce GPX4-regulated ferroptotic stress in tubular cells, potentially triggering the EMT process and contributing to kidney injury.
越来越多的证据表明，接触细颗粒物（PM2.5）会增加患肾病的风险。在本研究中，我们调查了PM2.5暴露对人近端肾小管上皮（HK-2）细胞的影响，发现它会升高铁死亡应激标志物，包括铁、活性氧（ROS）和丙二醛（MDA）增加，同时降低谷胱甘肽（GSH）水平。PM2.5促进这些细胞的上皮-间质转化（EMT），这与上皮形态的丧失、E-钙黏蛋白表达降低和α-平滑肌肌动蛋白（α-SMA）表达升高有关。值得注意的是，使用铁死亡特异性抑制剂（Fer-1）或线粒体ROS清除剂（Mito-Tempo）可观察到PM2.5诱导的EMT特征有所减少。此外，Fer-1有效对抗铁死亡应激并恢复PM2.5暴露细胞中谷胱甘肽过氧化物酶4（GPX4）的表达，这可能解释了其抑制PM2.5诱导的EMT的功效。相反，敲低GPX4会加剧PM2.5处理细胞中的EMT特征。进一步的研究表明，GPX4过表达可减轻PM2.5暴露后小鼠肾小管细胞中的EMT标志物，表明GPX4在减轻铁死亡应激中的作用，并可能预防PM2.5暴露引起的肾小管损伤。我们的研究强调，PM2.5可能在肾小管细胞中诱导GPX4调节的铁死亡应激，潜在地触发EMT过程并导致肾损伤。
