中药药物性急性肾损伤的网络毒理学及免疫机制研究  

Studies on the Network Toxicology and Immunological Mechanism of Chinese Herbal Medicine-Induced Acute Kidney Injury

作　　者：杨硕 栾相佳[2] 王连心[1] YANG Shuo;LUAN Xiangjia;WANG Lianxin(Institute of Basic Research in Clinical Medicine,China Academy of Chinese Medical Science;Guang'anmen Hospital,China Academy of Chinese Medical Science)

机构地区：[1]中国中医科学院中医临床基础医学研究所,北京100700 [2]中国中医科学院广安门医院

出　　处：《中医杂志》2024年第22期2347-2357,共11页Journal of Traditional Chinese Medicine

基　　金：国家重点研发计划(2022YFC3502004);国家自然科学基金(81973982);国家药品监督管理局药品监管科学体系建设重点项目(RS2024Z008)。

摘　　要：目的挖掘导致药物性急性肾损伤(DI-AKI)的潜在中药成分/中药并分析其致DI-AKI的可能机制,进一步探索中药导致DI-AKI与免疫系统的相关性。方法采用网络毒理学研究方法,通过DisGeNET、MalaCards、TTD、OMIM数据库收集DI-AKI相关靶点,再通过本草组鉴数据库、中国知网、万方数据知识服务平台、维普资讯中文期刊服务平台、PubMed进行中药导致DI-AKI成分筛选,选择口服生物利用度(OB)值≥20%的致DI-AKI中药成分,通过中药系统毒理学数据库筛选致DI-AKI的中药。使用Cytoscape v3.9.1构建DI-AKI靶点-中药成分-中药网络,计算该网络的拓扑属性得到关键的靶点、致DI-AKI中药成分及对应中药,对核心子网络靶点进行GO功能和KEGG通路富集分析,并使用免疫浸润分析及孟德尔随机化分析探索中药导致的DI-AKI与免疫系统的相关性。结果筛选出OB≥20%的致DI-AKI中药成分22个,其中生物碱类成分最多有5个,其次为蒽醌类和二萜类成分各3个。最终共收集到21味潜在的致DI-AKI中药,其中含马兜铃酸/马兜铃内酰胺类中药成分如朱砂莲、关木通、广防己、青木香等是导致DI-AKI的主要中药。TNF、TP53、IL6、HIF1A、BCL2等10个基因是DI-AKI发生发展过程中的枢纽基因。对核心子网络29个靶点GO功能富集发现上皮细胞增殖、凋亡信号通路的调控、血管生成、缺氧和氧化应激、血管生成等显著富集。KEGG通路中信号转导通路富集到了23个靶点和17条通路。免疫浸润分析结果显示,致DI-AKI中药与常规树突状细胞、巨噬细胞、中性粒细胞等呈正相关,而与CD4^(+)初始T细胞、CD8^(+)初始T细胞、未成熟的树突状细胞等呈负相关。孟德尔随机化分析结果显示,CD14^(+)、CD16^(+)单核细胞上的CD64可能成为急性肾损伤的危险因素,T细胞依赖性的CD4^(+)T细胞上的抗原受体为急性肾损伤的保护因素。结论通过网络毒理学研究逆向推导出了2Objective To explore potential herbal components/Chinese herbal medicines(CHM)leading to drug-induced acute kidney injury(DI-AKI)and analyse the possible mechanisms of DI-AKI,and to further explore the correlation between DI-AKI caused by Chinese herbal medicines and the immune system.Methods Using network toxicology research methods,DI-AKI-related targets were collected through DisGeNET,MalaCards,TTD,and OMIM databases,and then screened CHM components that caused DI-AKI through HERB database,China National Knowledge Infrastructure(CNKI),Wanfang Data Knowledge Service Platform,Wikipedia Chinese Journal Service Platform,and PubMed,selected with an oral bioavailability(OB)value≥20%,and screened CHM caused DI-AKI through traditional Chinese medicine system toxicology database.Cytoscape v3.9.1 was used to construct a DI-AKI target-CHM component-CHM network,and the topological properties of the network were calculated to obtain the key targets,DI-AKI-causing CHM components and the corresponding CHM,and the core sub-network targets were subjected to GO function and KEGG pathway enrichment analyses were conducted.The correlation between DI-AKI caused by CHM and the immune system was also explored using immune infiltration analysis and Mendelian randomisation analysis.Results There are 22 CHM components causing DI-AKI with OB≥20%were identified,among which alkaloids are the most abundant contained in 5 CHM components,followed by anthraquinones and diterpenes contained in 3 CHM components each.A total of 21 CHMs causing DI-AKI were finally collected,among which CHMs containing components of aristolochic acid/aristolactam such as Zhusha(Cinnabaris),Guanmutong(Isotrema manshuriense),Guangfangji(Isotrema fangchi)and Qingmuxiang(Inula helenium L.)were the main CHMs leading to DI-AKI.Ten genes including TNF,TP53,IL6,HIF1A,and BCL2 were the pivotal genes in the development of DI-AKI.GO functional enrichment of 29 targets in the core sub-network revealed significant enrichment in epithelial cell proliferation,regulation of a

关 键 词：药物性急性肾损伤 中药 网络毒理学 免疫浸润分析 孟德尔随机化 

分 类 号：R285[医药卫生—中药学]