中国血液净化

中国血液净化 ›› 2024, Vol. 23 ›› Issue (11): 849-853,858.doi: 10.3969/j.issn.1671-4091.2024.11.010

• 血管通路 • 上一篇    下一篇

基于生物信息学方法分析动静脉内瘘成熟机制中铁死亡的关键基因

金爱莲    汪 欢   

  1. 433000 仙桃，仙桃市第一人民医院1血液净化中心 2肾病内科
  • 收稿日期:2024-04-09 修回日期:2024-06-07 出版日期:2024-11-12 发布日期:2024-11-12
  • 通讯作者: 汪欢 E-mail:qk_xz123@163.com

Identification of ferroptosis-related genes in the mechanisms of arteriovenous fistula maturation based on bioinformatics analysis

JIN Ai-lian, WANG Huan   

  1. Blood Purification Center and 2Department of Nephrology, The First People's Hospital of Xiantao, Xiantao 433000, China
  • Received:2024-04-09 Revised:2024-06-07 Online:2024-11-12 Published:2024-11-12
  • Contact: 433000 仙桃，仙桃市第一人民医院1血液净化中心 2肾病内科 E-mail:qk_xz123@163.com

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摘要： 目的 动静脉内瘘(arteriovenous fistula,AVF)是血液透析患者首选的血管通路，但低成熟率严重影响终末期肾病患者的治疗。影响AVF成熟的分子机制目前仍不完全清楚。 方法 从Gene Expression Omnibus(GEO)数据库中下载AVF血管组织基因表达数据集(GSE220796和GSE119296)，从FerrDb数据库获取铁死亡数据集，鉴定差异的铁死亡相关基因(ferroptosis-related genes，FRGs)，并进行功能富集分析、蛋白质-蛋白质相互作用网络及枢纽基因鉴定，应用ROC曲线分析其诊断功效。通过免疫细胞浸润分析、转录因子预测及竞争内源性RNA(competing endogenous RNA,ceRNA)网络，研究低氧诱导因子1α(hypoxia-inducible factor-1alpha，HIF1A)潜在的生物学机制。 结果 共鉴定出70个差异FRGs(45个上调基因和25个下调基因)。功能富集分析提示对营养水平的反应、细胞对低氧水平的反应、调节平滑肌细胞增殖及叉头盒蛋白O(forkhead box protein O，FoxO)信号通路参与AVF成熟过程。鉴定出10个重要的枢纽基因，其中HIF1A在成熟AVF血管组织中高表达。ROC分析显示HIF1A评估AVF成熟的AUC为0.926。HIF1A与AVF血管组织中激活状态的树突细胞(r=0.663,P=0.003)及激活状态的肥大细胞(r=0.644,P=0.004)呈正相关。预测到叉头盒蛋白M1(forkhead box protein M1，FOXM1)为调控HIF1A表达的转录因子，并成功构建了一个包含71个长链非编码RNA(long non-coding RNA，lncRNA)、62个微小RNA(microRNAs，miRNA)和1个信使RNA(messenger RNA，mRNA)的竞争内源性RNA(competing endogenous RNA，ceRNA)网络。 结论 AVF成熟过程中血管组织中存在铁死亡，HIF1A是AVF成熟的潜在生物标志物。本研究为揭示HIF1A可提高AVF成熟的临床策略提供了理论依据。

关键词: 维持性血液透析, 动静脉内瘘, 铁死亡, 低氧诱导因子, 生物信息学分析

Abstract: Objective  Arteriovenous fistula (AVF) is currently the preferred vascular pathway for hemodialysis patients, but the low maturity rate seriously affects the treatment of end-stage renal disease patients. The molecular mechanisms that affect the maturation of AVF are not fully understood yet.  Methods  The gene expression profiles of the AVF vascular tissue (GSE220796 and GSE119296) were downloaded from the Gene Expression Omnibus (GEO) database and the ferroptosis-related genes (FRGs) were obtained from the FerrDb database. We identified differentially expressed FRGs, performed functional enrichment analysis, constructed protein-protein interaction (PPI) network, and identified hub genes. Receiver operator characteristic (ROC) curve was used to analyze the diagnostic efficacy. We also investigated the potential biological mechanisms of hypoxia-inducible factor-1 alpha (HIF1A) through immune cell infiltration analysis, transcription factor prediction, and competitive endogenous RNA (ceRNA) network construction. Results  A total of 70 differentially expressed FRGs were identified (45 upregulated genes and 25 downregulated genes). Functional enrichment analysis suggested that the response to nutrient level, cell response to low oxygen level, regulation of smooth muscle cell proliferation and forkhead box protein O (FoxO) signaling pathway were involved in the processes of AVF maturation. HIF1A was one of the 10 important hub genes and up-expressed in mature AVF vascular tissue. ROC curve analysis showed that area under the curve (AUC) value of HIF1A was 0.926 for diagnosing AVF maturation. HIF1A was found to be positively correlated with activated dendritic cells (r=0.663, P=0.003) and activated mast cells (r=0.644, P=0.004) in AVF vascular tissue. Forkhead box protein M1 (FOXM1) was predicted to be a transcription factor regulating HIF1A expression, and a ceRNA network containing 71 long non-coding RNA (lncRNAs), 62 microRNAs (miRNAs), and one messenger RNA (mRNA) was successfully constructed.  Conclusion  Our study elucidates the presence of ferroptosis in vascular tissues during AVF maturation, and HIF1A is a potential biomarker for AVF maturation. This study provides a theoretical basis that HIF1A may be a therapeutic target to improve AVF maturity.

Key words: Maintenance hemodialysis, Arteriovenous fistula, Ferroptosis, Hypoxia inducible factor, Bioinformatics analysis

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