Studies on the Network Toxicology and Immunological Mechanism of Chinese Herbal Medicine-Induced Acute Kidney Injury
Objective 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 net-work 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 sub-jected 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 randomis-ation 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(Cinnabar is),Guanmutong(Isotrema manshu-riense),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 apoptotic signalling pathways,angiogenesis,hypoxia and oxidative stress,and angio-genesis.Signal transduction pathways in the KEGG pathway were enriched to 23 targets and 17 pathways.The results of immune infiltration analysis showed that CHMs causing DI-AKI were positively correlated with conventional dendritic cells,macrophages,and neutrophils,and negatively correlated with CD4+initial T cells,CD8+initial T cells,and immature dendritic cells.Mendelian randomisation analysis showed that CD64 on CD14+and CD16+monocytes may be a risk factor for acute kidney injury,and T-cell-dependent antigen receptor on CD4+T cells is a protective factor for acute kidney injury.Conclusion Network toxicology studies identified 21 potential CHMs associated with DI-AKI,suggesting that their mechanisms may be closely linked to immune system activation through oxidative stress,autophagy,and apoptosis,which lead to inflammatory responses.The immune mechanism of DI-AKI induced by CHMs may involve elevated levels of immune cells,such as conventional dendritic cells,macrophages,and neutrophils,along-side a decline in natural killer T cells,helper T cells(types Ⅰ and Ⅱ),and monocytes,which have shown a causal relationship with acute kidney injury.he study provide a theoretical support for the study of CHM causing DI-AKI and also offer references for the CHM safety precise study and pharmacovigilance.
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