Key Genes and Biological Regulatory Mechanisms in Focal and Segmental Glomerulosclerosis: A Meta-Analysis and Validation of Expression Profiles

Abstract

Abstract Background: Focal segmental glomerulosclerosis (FSGS) - a histologic pattern of injury in the glomerulus - is one of the leading glomerular causes of ESRD worldwide. Despite vigorous research, the underlying biological alterations causing FSGS remain to be understood. Studying the variations in gene expression profiles is one of the promising approaches to have a holistic view of the FSGS molecular pathogenicity and help to discover key elements as potential therapeutic targets. The present work is a meta-analysis study including all the microarray gene expression profiles coming from glomerular samples of FSGS patients. Reaching to a consensus list of differentially expressed genes in FSGS condition, understanding the disease pathogenicity, and identification of novel therapeutic targets were the main aims of this study. Methods: After a vigorous search in GEO database and quality control assessments, seven gene expression datasets including GSE47183 (GPL14663), GSE47183 (GPL11670), GSE99340, GSE108109, GSE121233, GSE129973, and GSE104948 were selected for the meta-analysis. The random effect size method was applied and the identified meta-DEGs were considered for the construction of a regulatory network (STRING, MiRTarBase, and TRRUST), as well as performing different pathway enrichment analyses. The expression levels of several meta-DEGs (ADAMTS1, PF4, EGR1, and EGF) as angiogenesis regulators were analyzed using RT-qPCR method. Results: The identified 2898 meta-DEGs including 665 downregulated and 669 upregulated DEGs were subjected to different analyses. A co-regulatory network including 2859 DEGs, 2688 miRNAs, and 374 TFs was constructed and top molecules in the network (based on degree centrality) were identified. A part of the pathway enrichment analysis revealed a significant distortion in the angiogenesis regulatory pathways in the FSGS kidney. The results of RT-qPCR showed the presence of an imbalance in angiogenetic pathways by confirming the differential expression levels of ADAMTS1and EGR1 as the two main angiogenesis regulators in the FSGS condition. Conclusion: Despite providing a consensus list of differentially expressed genes in the FSGS condition, this meta-analysis revealed the existence of distortion in the angiogenesis-related pathways and factors in the FSGS kidney. Controlling such factors might be a possible way to hinder the progression of FSGS.