Bioinformatics Analysis Reveals a Shared Pathway for Common Forms of Adult Nephrotic Syndrome

Abstract

Key Points Dysregulation of the focal adhesion pathway is present in the three most common forms of glomerular disease, that is, Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease.Zyxin is seen to be upregulated in the glomerular compartment of patients with the three most common forms of glomerular disease. Background Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease are common causes of nephrotic syndrome. Although triggers for these diseases differ, disease progression may share common molecular mechanisms. The aim of this study was to investigate the presence of molecular pathways that are dysregulated across these glomerular diseases. Methods The gene expression dataset GSE200828 from the Nephrotic Syndrome Study Network study was obtained from the Gene Expression Omnibus database. R and Python packages, Cytoscape software, and online tools (DAVID and STRING) were used to identify core genes and topologically relevant nodes and molecular pathways. Single-cell RNA sequencing analysis was applied to identify the expression patterns of core genes across kidney cell types in glomerular compartments. Results A total of 1087 differentially expressed genes were identified, including 691 upregulated genes and 396 downregulated genes, which are common in all three forms of nephrotic syndrome compared with kidney donor controls (FDR P<0.01). A multiapproach bioinformatics analysis narrowed down to 28 similarly dysregulated genes across the three proteinuric glomerulopathies. The most topologically relevant nodes belonged to the adherens junction, focal adhesion, and cytoskeleton pathways, where zyxin covers all of those gene ontology terms. Conclusions We report that dysregulation of cell adhesion complexes was present in the three most common forms of glomerular disease. Zyxin could be a biomarker in all three common forms of nephrotic syndrome. If further functional studies confirm its role in their development, zyxin could be a potential therapeutic target.