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Epigenetically Regulated NOX4/NRF2 Axis Mediates PM2.5-Induced Ferroptosis and Inflammatory Response in Membranous
Yanhong Gao1, Yinfeng Guo1, Shaoyan Xu1
1Department of Nephrology, Affiliated Hospital of Jiaxing University (The First Hospital of Jiaxing), Zhejiang, China.
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.
Insights
Particulate matter 2.5 (PM2.5) worsens kidney damage in membranous nephropathy (MN) by promoting ferroptosis and inflammation via the NOX4/NRF2 pathway, offering new therapeutic targets for MN.
Area of Science:
- Nephrology
- Environmental Health
- Molecular Biology
Background:
- Membranous nephropathy (MN) is a leading cause of nephrotic syndrome.
- Particulate matter 2.5 (PM2.5) exposure is a growing environmental concern linked to various health issues, including kidney disease.
- The specific mechanisms by which PM2.5 exacerbates MN remain incompletely understood.
Purpose of the Study:
- To investigate the role and mechanism of ferroptosis in PM2.5-induced progression of MN.
- To elucidate the involvement of the NOX4/NRF2 signaling pathway and epigenetic regulation in PM2.5-mediated renal injury.
- To evaluate potential therapeutic interventions targeting ferroptosis and inflammation.
Main Methods:
- Established a cationic bovine serum albumin (cBSA)-induced mouse model of MN followed by PM2.5 exposure.
- Utilized in vitro models with MPC5 podocytes stimulated by puromycin aminonucleoside (PAN) and PM2.5.
- Assessed renal injury markers, inflammatory factors, ferroptosis indicators, and DNA methylation levels.
- Conducted in vitro rescue experiments using NOX4 inhibitor (GKT137831) and ferroptosis inhibitor (ferrostatin-1).
Main Results:
- PM2.5 exposure significantly aggravated renal injury, increased proteinuria, and elevated serum creatinine and blood urea nitrogen in MN mice.
- PM2.5 induced ferroptosis and inflammation in renal tissues, activating the NOX4/NRF2 axis.
- In vitro, PM2.5 increased NOX4 expression and reduced its methylation in podocytes, an effect reversed by DNMT1.
- Inhibitors of NOX4 and ferroptosis attenuated PM2.5-induced podocyte injury and inflammatory responses.
Conclusions:
- PM2.5 exacerbates renal injury in MN by promoting ferroptosis and inflammation.
- The NOX4/NRF2 axis, epigenetically regulated by DNA methylation, is a key mechanism in PM2.5-induced renal damage.
- Targeting ferroptosis and the NOX4/NRF2 pathway presents a potential therapeutic strategy for mitigating PM2.5-related kidney injury in MN.
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