FOSB在IgA肾病及其他常见肾脏病肾组织中的表达特征

doi:10.13481/j.1671-587X.20250515

摘要/Abstract

摘要：

目的评估FBJ鼠科骨肉瘤病毒癌基因同源物B（FOSB）基因在免疫球蛋白A肾病（IgAN）和常见慢性肾脏病（CKD）中的表达特征，探讨其作为潜在关键候选基因或生物标志物的价值。方法从基因表达综合数据库（GEO）中下载IgAN、糖尿病肾病（DKD）、膜性肾病（MN）和微小病变肾病（MCD）肾小球样本的RNA测序数据集。采用最小绝对收缩和选择算子（LASSO）回归、随机森林（RF）和支持向量机（SVM）机器学习方法筛选相应CKD的特征基因。对IgAN的特征基因进行基因本体论（GO）功能富集和京都基因与基因组百科全书（KEGG）信号通路富集分析。采用pROC包绘制受试者工作特征（ROC）曲线评估特征基因对IgAN的诊断效能，并筛选诊断效能最高的基因进行基因集富集分析（GSEA），分析其与IgAN核心免疫细胞浸润的相关性。基于Nephroseq v5平台分析肾组织中FOSB表达水平与肾功能的关系。收集IgAN、DKD、MN和MCD患者肾脏组织标本各5例及5例癌旁正常肾组织标本（对照组），采用免疫组织化学染色法检测各组肾组织中FOSB蛋白表达水平。结果共筛选出110个IgAN肾小球差异表达基因（DEGs），其中FOSB、NR4A2和DUSP1为特征基因。IgAN组FOSB mRNA表达水平明显低于健康对照组（P<0.05）。GO功能富集分析，IgAN特征基因主要富集于多巴胺生物合成、中脑多巴胺能神经元分化、肽基丝氨酸/苏氨酸去磷酸化及对皮质酮的反应等生物过程。KEGG信号通路富集分析，IgAN特征基因主要富集于可卡因成瘾、安非他命成瘾、白细胞介素17（IL-17）信号通路、醛固酮合成与分泌和5-羟色胺能突触等信号通路。ROC曲线分析，FOSB对IgAN具有良好的诊断效能。GSEA分析，FOSB高表达组中，DEGs在精氨酸和脯氨酸代谢、丁酸代谢、成红细胞白血病病毒癌基因同源物（ERBB）信号通路、丝裂原活化蛋白激酶（MAPK）信号通路和果糖及甘露糖代谢等通路显著富集；FOSB低表达组中，DEGs在同种异体移植排斥反应、细胞外基质受体相互作用和1型糖尿病等通路显著富集。免疫细胞浸润分析，自然杀伤细胞、中性粒细胞和M1型巨噬细胞是IgAN的核心免疫细胞，且FOSB表达与中性粒细胞浸润呈正相关关系（r=0.42，P<0.05）。免疫组织化学检测，与对照组比较，IgAN、DKD、MN和MCD组患者肾小球组织中FOSB蛋白表达水平均明显降低（P<0.05）。结论 FOSB基因在IgAN、DKD、MN和MCD患者肾小球组织中呈低表达，其可能是IgAN潜在的生物标志物。

关键词: FBJ鼠科骨肉瘤病毒癌基因同源物B, 免疫球蛋白A肾病, 生物信息学, 免疫组织化学, 慢性肾脏病, 候选基因

Abstract:

Objective To evaluate the expression characteristics of the FBJ murine osteosarcoma viral oncogene homolog B（FOSB） gene in immunoglobulin A nephropathy （IgAN） and common chronic kidney diseases （CKDs）， and to determine its value as a potential key candidate gene or biomarker. Methods The RNA sequencing datasets for IgAN，diabetic kidney disease （DKD）， membranous nephropathy（MN）， and minimal change disease（MCD） glomerular samples were downloaded from the Gene Expression Omnibus（GEO） database. The feature genes for CKD were identified using machine learning methods including least absolute shrinkage and selection operator（LASSO） regression， random forest（RF）， and support vector machine（SVM）. Gene Ontology（GO） functional enrichment and Kyoto Encyclopedia of Genes and Genomes（KEGG） signaling pathway enrichment analyses were performed on the identified IgAN feature genes. The “pROC” package was used to plot the receiver operating characteristic（ROC） curves to evaluate the diagnostic efficacy of IgAN feature genes.The gene with the highest diagnostic value was selected for Gene Set Enrichment Analysis（GSEA） and correlation analysis with core immune cells in IgAN. Clinical correlation analysis between the FOSB expression level in kidney tissue and renal function was performed using the Nephroseq v5 platform. Kidney tissue samples were collected from 5 cases of IgAN patients，DKD patients， MCD patients， and MN patients，respectively，along with 5 samples of adjacent normal kidney tissues （control group）. Immunohistochemistry staining method was used to detect the expression levels of FOSB protein in tissue samples in various groups. Results A total of 110 differentially expressed genes（DEGs） were identified in IgAN glomeruli， among which FOSB， NR4A2， and DUSP1 were identified as the feature genes. Compared with control group， the expression level of FOSB mRNA in IgAN group was significantly decreased（P<0.05）. The GO fuctional enrichment analysis results revealed that these IgAN feature genes were primarily enriched in biological processes related to dopamine biosynthesis，midbrain dopaminergic neuron differentiation， peptidyl-serine/threonine dephosphorylation， and response to corticosterone. The KEGG signaling pathway enrichment analysis results showed that the DEGs were significantly enriched in cocaine addiction，amphetamine addiction， interleukin 17 （IL-17） signaling pathway，aldosterone synthesis and secretion， and serotonergic synapse. The ROC curve analysis results demonstrated that FOSB showed high diagnostic accuracy for IgAN. GSEA analysis revealed that arginine and proline metabolism，butyrate metabolism， erythroblastic leukemia viral oncogene homolog（ERBB） signaling pathway，mitogen-activated protein kinase （MAPK） signaling pathway， and fructose and mannose metabolism pathways were enriched in FOSB high-expression group， while allograft rejection， extracellular matrix receptor interaction，and type 1 diabetes pathways were significantly enriched in FOSB low-expression group. The immune cell infiltration analysis results identified natural killer cells， neutrophils，and M1 macrophages as core immune cells in IgAN， and the expression of FOSB gene was positively correlated with neutrophil infiltration （r=0.42， P<0.05）. The immunohistochemistry analysis results demonstrated that compared with control group，the expression level of FOSB protein in glomeruli of the patients in IgAN， DKD， MN， and MCD groups were significantly decreased（P<0.05）. Conclusion The expressions of FOSB gene in the glomeruli tissue of IgAN，DKD，MN，and MCD patients ware decreased， suggesting FOSB may represent a potential biomarker for IgAN.

Key words: FBJ murine osteosarcoma viral oncogene homolog B, Immunoglobulin A nephropathy, Bioinformatics analysis, Immunohistochemistry, Chronic kidney disease, Candidate gene

中图分类号:

R692.6

梁鱼,于金宇,许钟镐,王婉宁. FOSB在IgA肾病及其他常见肾脏病肾组织中的表达特征[J]. 吉林大学学报(医学版), 2025, 51(5): 1281-1292.

Yu LIANG,Jinyu YU,Zhonggao XU,Wanning WANG. Expression characteristics of FOSB in kidney tissue from IgA nephropathy and other common kidney diseases[J]. Journal of Jilin University(Medicine Edition), 2025, 51(5): 1281-1292.

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Group	IgAN			DKD
Group	Training set		Validation set	Training set		Validation set
Dataset	GSE93798	GSE104948 (GPL24120)	GSE99340 (GPL19184)	GSE30528	GSE96804	GSE30122
Healthy control samples	22	2	8	13	20	26
Disease samples	20	27	26	9	41	9