表观遗传调控的NOX4/NRF2轴介导PM2.5诱导的膜性肾病铁死亡和炎症反应
Epigenetically Regulated NOX4/NRF2 Axis Mediates PM2.5-Induced Ferroptosis and Inflammatory Response in Membranous Nephropathy.
摘要(中文译文)
本研究旨在探讨铁死亡在细颗粒物2.5（PM2.5）诱导的膜性肾病（MN）进展中的参与及其机制。建立阳离子牛血清白蛋白（cBSA）诱导的MN小鼠模型，随后进行PM2.5暴露。采用血液学指标、苏木精-伊红染色和过碘酸-雪夫染色评估肾损伤。通过酶联免疫吸附试验和蛋白质印迹法评估炎症因子和铁死亡指标水平。通过嘌呤霉素氨基核苷（PAN）刺激分化的MPC5足细胞，随后进行PM2.5处理，建立体外MN样模型。采用定量甲基化特异性聚合酶链反应测定DNA甲基化水平。足细胞经GKT137831或ferrostatin-1预处理进行体外挽救实验。PM2.5暴露显著加重了cBSA诱导的MN小鼠的肾损伤，表现为尿总蛋白、血清肌酐和血尿素氮水平升高，IgG和C3沉积以及组织病理学改变。此外，PM2.5增加了cBSA诱导的MN小鼠肾组织中铁死亡和炎症水平，并伴有NOX4/NRF2轴的激活。在PAN和PM2.5共处理的MPC5细胞中，NOX4表达升高，而其甲基化水平降低。DNMT1过表达逆转了PM2.5诱导的NOX4甲基化抑制。值得注意的是，GKT137831或ferrostatin-1预处理减轻了PM2.5介导的细胞活力下降，并阻止了PAN刺激的MPC5细胞中铁死亡和促炎表型的激活。总之，PM2.5通过表观遗传调控的NOX4/NRF2轴促进铁死亡和炎症，从而加重MN中的肾损伤。
Abstract
This study aims to explore the involvement and mechanism of ferroptosis in particulate matter 2.5 (PM2.5)-induced membranous nephropathy (MN) progression. A cationic bovine serum albumin (cBSA)-induced mouse model of MN was established, followed by PM2.5 exposure. Renal injury was assessed using hematological indicators, hematoxylin-eosin staining, and periodic acid-Schiff staining. Levels of inflammatory factors and ferroptosis indicators were assessed by enzyme-linked immunosorbent assay and western blot. An in vitro MN-like model was created by stimulating differentiated MPC5 podocytes with puromycin aminonucleoside (PAN), followed by PM2.5 treatment. DNA methylation levels were determined using quantitative methylation-specific polymerase chain reaction. Podocytes were pretreated with GKT137831 or ferrostatin-1 for in vitro rescue experiments. PM2.5 exposure significantly aggravated renal injury in cBSA-induced MN mice, as indicated by increased levels of urinary total protein, serum creatinine, and blood urea nitrogen; the deposition of IgG and C3; and histopathological alterations. Furthermore, PM2.5 increased levels of ferroptosis and inflammation in the renal tissues of cBSA-induced MN mice, accompanied by the activation of the NOX4/NRF2 axis. In PAN and PM2.5 co-treated MPC5 cells, NOX4 expression was elevated, whereas its methylation level was reduced. Overexpression of DNMT1 reversed the PM2.5-induced suppression of NOX4 methylation. Notably, pretreatment with GKT137831 or ferrostatin-1 attenuated the PM2.5-mediated reduction in cell viability and prevented the activation of ferroptosis and pro-inflammatory phenotypes in PAN-stimulated MPC5 cells. In conclusion, PM2.5 promotes ferroptosis and inflammation through an epigenetically regulated NOX4/NRF2 axis, thereby exacerbating renal injury in MN.
如何引用
AMA
Yanhong Gao, Yinfeng Guo, Shaoyan Xu, Min Zhang, Yanxia Rui, Shujun Pan, et al. Epigenetically Regulated NOX4/NRF2 Axis Mediates PM2.5-Induced Ferroptosis and Inflammatory Response in Membranous Nephropathy.. Journal of applied toxicology : JAT. 2026; doi:10.1002/jat.70354.
APA
Yanhong Gao, Yinfeng Guo, Shaoyan Xu, Min Zhang, Yanxia Rui, Shujun Pan, et al (2026). Epigenetically Regulated NOX4/NRF2 Axis Mediates PM2.5-Induced Ferroptosis and Inflammatory Response in Membranous Nephropathy.. Journal of applied toxicology : JAT. https://doi.org/10.1002/jat.70354
GB/T 7714
Yanhong Gao, Yinfeng Guo, Shaoyan Xu, Min Zhang, Yanxia Rui, Shujun Pan, et al. Epigenetically Regulated NOX4/NRF2 Axis Mediates PM2.5-Induced Ferroptosis and Inflammatory Response in Membranous Nephropathy.[J]. Journal of applied toxicology : JAT, 2026 doi:10.1002/jat.70354.
在 PubMed增强版 阅读全文
翻译全文 · AI 文献问答 · PDF 原文下载 · 引用导出