Construction of a TF-miRNA-mRNA Regulatory Network for Diabetic Nephropathy.

Abstract

This study aims to elucidate the microRNA (miRNA)-messenger RNA (mRNA)-transcription factors (TFs) network relevant to diabetic nephropathy (DN). To investigate the molecular mechanisms underlying DN, we conducted an extensive analysis using a Gene Expression Omnibus (GEO) database, specifically GSE51784, GSE30528, GSE30529 and GSE1009. RNA samples from 66 subjects were analysed to identify differentially expressed mRNAs (DEGs) and microRNAs (DEMs) between individuals with DN and healthy controls. The data underwent preprocessing, followed by Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Set Enrichment Analysis (GSEA) to unveil enriched pathways. Additionally, we constructed protein-protein interaction networks and subnetworks of modules to identify key molecular players. A total of 163 DEMs and 188 DEGs were identified among the four datasets. Furthermore, we identified 37 hub genes with high connectivity and four TFs, namely E1A Binding Protein P300 (EP300), SP100 Nuclear Antigen (SP100), Nuclear Receptor Subfamily 6 Group A Member 1 (NR6A1) and Jun Dimerization Protein 2 (JDP2), which may play crucial roles in the molecular pathogenesis of DN. Additionally, we constructed a co-regulatory network involving miRNAs, mRNAs and TFs, revealing potential involvement of pathways such as the Mitogen-Activated Protein Kinase (MAPK) signalling pathway, phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signalling pathway and metabolic pathways in the pathogenesis of DN. Finally, using a docking model, we established drug-gene interactions involving key genes in the network, providing potential insights into therapeutic options. This study explores a gene regulation network of miRNA-mRNA-TFs, identifying potential molecular targets in the aetiology of DN. It also suggests potential targets for genetic counselling and prenatal diagnosis for DN.