Identification of the Crucial Gene in Overflow Arteriovenous Fistula by Bioinformatics Analysis.

Zhengde Zhao,Liangzhu Hu,Yangdong Liu,Qining Fu

doi:10.3389/fphys.2021.621830

Abstract

Objective: The aim was to study the preliminary screening of the crucial genes in intimal hyperplasia in the venous segment of arteriovenous (AV) fistula and the underlying potential molecular mechanisms of intimal hyperplasia with bioinformatics analysis.Methods: The gene expression profile data (GSE39488) was analyzed to identify differentially expressed genes (DEGs). We performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of DEGs. Gene set enrichment analysis (GSEA) was used to understand the potential activated signaling pathway. The protein–protein interaction (PPI) network was constructed with the STRING database and Cytoscape software. The Venn diagram between 10 hub genes and gene sets of 4 crucial signaling pathways was used to obtain core genes and relevant potential pathways. Furthermore, GSEAs were performed to understand their biological functions.Results: A total of 185 DEGs were screened in this study. The main biological function of the 111 upregulated genes in AV fistula primarily concentrated on cell proliferation and vascular remodeling, and the 74 downregulated genes in AV fistula were enriched in the biological function mainly relevant to inflammation. GSEA found four signaling pathways crucial for intimal hyperplasia, namely, MAPK, NOD-like, Cell Cycle, and TGF-beta signaling pathway. A total of 10 hub genes were identified, namely, EGR1, EGR2, EGR3, NR4A1, NR4A2, DUSP1, CXCR4, ATF3, CCL4, and CYR61. Particularly, DUSP1 and NR4A1 were identified as core genes that potentially participate in the MAPK signaling pathway. In AV fistula, the biological processes and pathways were primarily involved with MAPK signaling pathway and MAPK-mediated pathway with the high expression of DUSP1 and were highly relevant to cell proliferation and inflammation with the low expression of DUSP1. Besides, the biological processes and pathways in AV fistula with the high expression of NR4A1 similarly included the MAPK signaling pathway and the pathway mediated by MAPK signaling, and it was mainly involved with inflammation in AV fistula with the low expression of NR4A1.Conclusion: We screened four potential signaling pathways relevant to intimal hyperplasia and identified 10 hub genes, including two core genes (i.e., DUSP1 and NR4A1). Two core genes potentially participate in the MAPK signaling pathway and might serve as the therapeutic targets of intimal hyperplasia to prevent stenosis after AV fistula creation.

Highlights

Arteriovenous (AV) fistula is a preferred type of vascular access for hemodialysis in patients with end-stage renal disease given its superior patency rate
The DAVID database was used for the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of 111 upregulated differentially expressed genes (DEGs) and 74 downregulated DEGs in the AV fistula group compared with the control group, respectively
For the upregulated genes in the AV fistula group compared with the control group, the top five enriched GO terms were “skeletal muscle cell differentiation,” “cell adhesion,” “signal transduction,” “positive regulation of natural killer cell chemotaxis,” and “angiogenesis” in Biological Processes (BP) category, and “extracellular region,” “brush border,” “clathrincoated vesicle,” and “proteinaceous extracellular matrix” in Cellular Component (CC) category, and “CCR1 chemokine receptor binding,” “CCR5 chemokine receptor binding,” “integrin binding,” “heparin binding,” and “phosphatidylinositol binding” in Molecular Function (MF) category

Summary

Introduction

Arteriovenous (AV) fistula is a preferred type of vascular access for hemodialysis in patients with end-stage renal disease given its superior patency rate. Various studies reported a poor 1-year primary patency rate of AV fistula not exceeding 60–65% (Dixon et al, 2002; Tordoir et al, 2003; Arhuidese et al, 2018). 40% of AV fistula are no longer functional 2 years after placement (Gibson et al, 2001; Arhuidese et al, 2018). Percutaneous balloon angioplasty (PTA) is usually applied to maintain AV fistula patency because it reduces the need for surgical intervention, AV fistula abandonment, or AV fistula creation of more costly AV graft, given the historically greater need for maintenance intervention (Stolic, 2013). It is relatively important to prevent stenosis after AV fistula creation and to prolong the time of primary stenosis occurrence for the management of AV fistula

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Discussion

Conclusion