Xie Liyuan, Qiu Xianying, Jia Junya, Yan Tiekun, Xu Pengcheng
Department of Nephrology, Tianjin Medical University General Hospital, Tianjin, P.R. China.
Ren Fail. 2025 Dec;47(1):2499905. doi: 10.1080/0886022X.2025.2499905. Epub 2025 May 14.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease often leading to rapidly progressive glomerulonephritis. Oxidative stress plays a critical role in the development and progression of ANCA-associated glomerulonephritis (AAGN), but the underlying mechanisms remain poorly understood. Targeting genes related to oxidative stress may provide novel insights and supplementary therapeutic benefits for AAGN. In the current study, we obtained differentially expressed genes from AAGN-related microarray datasets in the Gene Expression Omnibus database, and oxidative stress-related genes (OSRGs) from the GeneCards and Gene Ontology databases to identify differentially expressed OSRGs. Then, by integrating weighted gene co-expression network analysis, and machine learning algorithms, we identified four upregulated hub OSRGs (all < 0.01) with strong diagnostic potential (all AUC > 0.9)-CD44, ITGB2, MICB, and RAC2 - in the AAGN glomerular training dataset GSE104948 and validation dataset GSE108109, along with two hub OSRGs (all < 0.05) with better diagnostic potential (all AUC > 0.7) - upregulated gene VCAM1 and downregulated gene VEGFA-in the AAGN tubulointerstitial training dataset GSE104954 and validation dataset GSE108112. The GSEA analysis suggested that these hub genes may play a role in inflammatory and immune response processes. Moreover, we constructed regulatory networks and identified drugs that potentially target these hub genes. It's to be noted that RAC2 and ITGB2 were associated with cyclophosphamide in the AAGN glomerular compartment, while VCAM1 and VEGFA were associated with dexamethasone in the tubulointerstitial compartment. This study offers novel insights into immune-associated OSRGs within the glomerular and tubulointerstitial compartments of AAGN which may serve as innovative targets for diagnosing and treating AAGN.
抗中性粒细胞胞浆抗体（ANCA）相关血管炎（AAV）是一种全身性自身免疫性疾病，常导致快速进展性肾小球肾炎。氧化应激在ANCA相关肾小球肾炎（AAGN）的发生和发展中起关键作用，但其潜在机制仍知之甚少。靶向与氧化应激相关的基因可能为AAGN提供新的见解和辅助治疗益处。在本研究中，我们从基因表达综合数据库中与AAGN相关的微阵列数据集中获取差异表达基因，并从基因卡片和基因本体数据库中获取氧化应激相关基因（OSRGs），以识别差异表达的OSRGs。然后，通过整合加权基因共表达网络分析和机器学习算法，我们在AAGN肾小球训练数据集GSE104948和验证数据集GSE108109中鉴定出四个上调的核心OSRGs（所有P值均<0.01），具有很强的诊断潜力（所有曲线下面积均>0.9）——CD44、ITGB2、MICB和RAC2，以及在AAGN肾小管间质训练数据集GSE104954和验证数据集GSE108112中两个具有较好诊断潜力（所有曲线下面积均>0.7）的核心OSRGs（所有P值均<0.05）——上调基因VCAM1和下调基因VEGFA。基因集富集分析表明，这些核心基因可能在炎症和免疫反应过程中发挥作用。此外，我们构建了调控网络并鉴定了可能靶向这些核心基因的药物。需要注意的是，RAC2和ITGB2在AAGN肾小球部分与环磷酰胺有关，而VCAM1和VEGFA在肾小管间质部分与地塞米松有关。本研究为AAGN肾小球和肾小管间质部分内与免疫相关的OSRGs提供了新的见解，这些OSRGs可能作为诊断和治疗AAGN的创新靶点。
