Integrated transcriptomic analysis with experimental validation reveals the potential pathogenic role of VSIG4 in idiopathic membranous nephropathy

This study aimed to investigate key genes driving idiopathic membranous nephropathy (IMN) pathogenesis, assess their expression profiles and clinical value, and investigate their functional roles in podocyte injury. The LIMMA package in R was used to analyze the Gene Expression Omnibus (GEO) datasets GSE73953 (blood-derived) and GSE216841 (glomerular-derived) to identify differentially expressed genes (DEGs). DEGs and overlapping DEGs (ODEGs) between the two datasets were subjected to GO and KEGG enrichment analyses. Subsequently, the ODEGs were correlated with key clinical indicators using the Nephroseq database to prioritize candidate genes, which were then validated by quantitative real-time PCR (qRT-PCR) in peripheral blood mononuclear cells (PBMCs) from IMN patients. Following confirmation, key gene's associations with clinical indicators and disease severity were analyzed, and its diagnostic value was evaluated using receiver operating characteristic (ROC) curve analysis. Finally, an in vitro podocyte injury model was established using C5b-9, and the role of the key gene in podocytes was preliminarily explored through transfection and western blotting. Differential expression analysis of the blood-derived dataset GSE73953 and glomerular-derived dataset GSE216841 identified 1138 and 1291 DEGs, respectively, yielding 57 ODEGs. Correlation of ODEGs with key clinical indicators via Nephroseq prioritized five genes: VSIG4, TNFRSF12A, B3GNT7, RAB27A, and ALPK1. Clinical validation showed that VSIG4 was significantly elevated in IMN patient PBMCs compared with healthy controls and IgA nephropathy patients (P < 0.05), and was correlated with clinical parameters. Moreover, in vitro experiments preliminarily suggested that silencing VSIG4 may alleviate podocyte injury in IMN. These results indicated that VSIG4 is upregulated in IMN patients, correlates with disease severity, and may contribute to podocyte injury, thereby laying a foundation for future mechanistic studies and therapeutic development.