Bioinformatic Analysis Reveals VEGFA Promotes the Occurrence of PLA2R-associated Idiopathic Membranous Nephropathy by Angiogenesis via PI3K/AKT Signaling Pathway

Backround: PLA2R-associated IMN covers 70% of IMN, which is one of the main types of chronic kidney disease in adults and one of the most common causes of end‑stage renal disease. Vascular endothelial growth factor A (VEGFA), a homodimeric vasoactive glycoprotein, is the key mediator of angiogenesis, which lead to numerous kidney diseases, including TSHD7A-associated IMN. However, the role of VEGFA in PLA2R-associated IMN is still poorly understood.Methods: We downloaded the microarray data GSE115857 from GEO. The DEGs were identified with R software, and the functional and pathway enrichment analysis of DEGs was performed utilizing the DAVID and Cytoscape ClueGo plug-in. A comprehensive list of interacting DEGs was constructed using the STRING database and visualized by Cytoscape software. The Cytoscape MCODE and cytoHubba plug-in were used to identify clustered sub-networks, and hub genes from the protein-protein interaction network. Gene set enrichment analysis (GSEA) was used to identify signaling pathway in IMN. Results: There were 1422 genes (952 up-regulated genes and 470 down-regulated genes) were identified as DEGs in GSE115857. The BP of DEGs in GSE115857 was clustered in regulation of transcription from RNA polymerase II promoter, positive regulation of nuclear-transcribed mRNA poly(A) tail shortening, cell adhesion et al. The KEGG pathway of DEGs in GSE115857 was clustered in Rheumatoid arthritis, ABC transporters, PI3K/AKT signaling pathway et al. Then we got a huge PPI network from STRING. 6 modules were screen out to study the functional changes in IMN. The KEGG pathway of module 3 was enriched in soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) interactions in vesicular transport. There were 3 hub genes screened out, namely, VEGFA, JUN,and FOS. Following the random walk, all genes were ranked and GSEA analysis showed that the signaling pathway of DEGs in GSE115857 was focused on angiogenesis, in which VEGFA acts as a core gene. CONCLUSION: In summary, this study reveals VEGFA promotes PLA2R-associated IMN by stimulating angiogenesis via PI3K/AKT signaling. Moreover, SNARE interactions in vesicular transport was involved in the development of PLA2R-associated IMN, which may offer a novel therapeutic strategy in treatment of IMN.