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Screening potential diagnostic biomarkers for PLA2R‑associated idiopathic membranous nephropathy by WGCNA analysis
Jinxu Huang1, Yaqing Huang2, Xiaoling Zeng2
1Department of Laboratory Medicine, Xiamen Key Laboratory of Precision Diagnosis and Treatment of Chronic Kidney Disease, The Fifth Hospital of Xiamen, Xiamen, Fujian, China.
Abstract:
Adult nephrotic syndrome is primarily caused by membranous nephropathy (MN), with idiopathic membranous nephropathy (IMN) being a prominent subtype. The onset of phospholipase A2 receptor (PLA2R1)-associated IMN is critically linked to M-type PLA2R1 exposure, yet the mechanism underlying glomerular injury remains unclear. In this study, membranous nephropathy datasets (GSE115857, GSE200828) were retrieved from GEO. Differential gene expression was analyzed using the 'limma' R package. WGCNA filtered PLA2R-related modules and intersected genes. LASSO regression, evaluated by ROC analysis, identified characteristic genes. Binomial logistic regression assessed their association with IMN. Validation was performed in the GSE133288 dataset. IHC and qRT-PCR detected characteristic gene expression in PLA2R-positive patients. This study identified elevated PLA2R expression in IMN patients among 117 DEGs. PPI analysis suggested enrichment in Golgi membranes, co-regulation, and glucocorticoid responsiveness, implicating the PPAR pathway by KEGG. WGCNA revealed a 440-gene brown module associated with IMN-PLA2R, with ECM1, SLC19A2, RASD1, FOSB, KDELR3, ZFP36, and ELF4 highlighted as diagnostic markers by ROC analysis. Clinical validation confirmed ECM1 upregulation increased IMN risk, while upregulation of SLC19A2, ZFP36, RASD1, and FOSB decreased it. ECM1 positively correlated with PLA2R, whereas SLC19A2, ZFP36, and FOSB negatively correlated. IHC analysis demonstrated consistent gene expression patterns in IMN tissues, with podocyte exposure to PLA2R-positive serum reducing viability and increasing apoptosis. Functional studies, prompted by RASD1 downregulation, revealed enhanced cell activity and reduced apoptosis upon RASD1 overexpression compared to the Serum + Ov-NC control. Collectively, this study identified diagnostic markers for PLA2R-related IMN, offering novel therapeutic targets for the treatment of IMN.
Insights
This study identifies key diagnostic markers for phospholipase A2 receptor (PLA2R)-associated idiopathic membranous nephropathy (IMN). These findings offer new therapeutic targets for treating this kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Genomics
Background:
- Adult nephrotic syndrome is often caused by membranous nephropathy (MN), particularly idiopathic membranous nephropathy (IMN).
- Phospholipase A2 receptor (PLA2R)-associated IMN is common, but the mechanisms of glomerular injury are not fully understood.
- Identifying specific biomarkers is crucial for diagnosing and treating PLA2R-related IMN.
Purpose of the Study:
- To identify diagnostic gene markers for PLA2R-associated IMN.
- To investigate the underlying molecular mechanisms of glomerular injury in IMN.
- To explore potential therapeutic targets for IMN.
Main Methods:
- Differential gene expression analysis of membranous nephropathy datasets (GSE115857, GSE200828).
- Weighted Gene Co-expression Network Analysis (WGCNA) and LASSO regression to identify characteristic genes.
- Binomial logistic regression, ROC analysis, immunohistochemistry (IHC), and qRT-PCR for validation.
- In vitro studies on podocyte viability and apoptosis.
Main Results:
- Elevated PLA2R expression and 117 differentially expressed genes (DEGs) were identified in IMN patients.
- WGCNA highlighted a module associated with IMN-PLA2R, with ECM1, SLC19A2, RASD1, FOSB, KDELR3, ZFP36, and ELF4 identified as diagnostic markers.
- Clinical validation confirmed ECM1 upregulation increases IMN risk, while SLC19A2, ZFP36, RASD1, and FOSB upregulation decrease it.
- PLA2R-positive serum reduced podocyte viability and increased apoptosis; RASD1 overexpression enhanced cell activity and reduced apoptosis.
Conclusions:
- Novel diagnostic markers, including ECM1, SLC19A2, RASD1, FOSB, ZFP36, KDELR3, and ELF4, were identified for PLA2R-related IMN.
- The study implicates the PPAR pathway and highlights the role of ECM1 and RASD1 in IMN pathogenesis.
- These findings provide potential therapeutic targets for IMN treatment.
