不同来源供肾缺血-再灌注损伤核心靶点的鉴定和诊断模型的构建

Identification of core targets and construction of diagnostic models for ischemia-reperfusion injury in donor kidneys from different sources

    摘要
  • 摘要:
    目的 探索不同来源供者肾移植缺血-再灌注损伤（IRI）的潜在作用靶点。
    方法 以不同来源供者肾移植IRI转录组测序数据GSE43974为基础，利用加权基因共表达网络分析（WGCNA）、蛋白质相互作用（PPI）鉴定其中的Hub基因并探索其表达景观。利用列线图模型评估Hub基因的诊断价值。利用数据集GSE30718对Hub基因的诊断价值进行验证。通过免疫浸润分析探索Hub与免疫细胞浸润的相关性。采用小鼠肾移植IRI模型对Hub基因的表达进行验证。
    结果 最终共鉴定出5个Hub基因，分别为PPP1CC、GART、BIRC6、PMSD11和TMEM192。列线图模型结果显示Hub基因对不同来源供者肾移植IRI具有良好的诊断价值。免疫浸润分析提示多种免疫细胞在不同来源供者肾移植IRI中具有差异，且Hub基因与多种免疫细胞浸润调控存在相关性。肾移植组和假手术组小鼠肾脏组织间共390个差异基因，基因本体（GO）富集分析发现差异基因主要与氧化应激、炎症、细胞焦亡等生物学功能有关；京都基因与基因组百科全书（KEGG）富集分析发现谷胱甘肽代谢、中性粒细胞胞外诱捕网等信号通路富集。转录组测序结果显示，5个Hub基因在两组肾组织中表达差异均有统计学意义（均为P<0.05）。
    结论 在不同来源供者肾移植IRI中鉴定出5个Hub基因，而谷胱甘肽代谢、中性粒细胞胞外诱捕网形成可能与肾移植IRI有关。

     

    Abstract:
    Objective To explore the potential functional targets of ischemia-reperfusion injury (IRI) in renal allografts derived from different donor sources.
    Methods Based on the transcriptome sequencing dataset GSE43974 of kidney transplantation IRI from different donor sources, weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis were performed to screen Hub genes and characterize their expression profiles. A nomogram model was established to evaluate the diagnostic efficacy of these Hub genes, which was further validated using the dataset GSE30718. Immune infiltration analysis was conducted to clarify the correlations between Hub genes and immune cell infiltration. A mouse kidney transplantation IRI model was adopted to verify the expression levels of Hub genes in vivo.
    Results A total of five Hub genes were finally identified, namely PPP1CC, GART, BIRC6, PMSD11 and TMEM192. Nomogram analysis confirmed that these Hub genes possessed favorable diagnostic performance for kidney transplantation IRI in kidneys from different donors. Immune infiltration analysis revealed distinct infiltration patterns of various immune cells in IRI kidneys from different donors, and Hub genes were closely correlated with the regulation of multiple immune cell infiltration. A total of 390 differentially expressed genes were screened between renal tissues of mice in the kidney transplantation group and sham operation group. Gene Ontology (GO) enrichment analysis indicated that these differentially expressed genes were mainly enriched in biological processes including oxidative stress, inflammation and pyroptosis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed significant enrichment in glutathione metabolism, neutrophil extracellular trap formation and other signaling pathways. Transcriptome sequencing verified that the expression levels of the five Hub genes were significantly different between the two groups (all P < 0.05).
    Conclusions Five Hub genes are identified in kidney transplantation IRI using donor kidneys from different sources. Glutathione metabolism and neutrophil extracellular trap formation may participate in the pathogenesis of kidney transplantation IRI.

     

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