Studies on the Network Toxicology and Immunological Mechanism of Chinese Herbal Medicine-Induced Acute Kidney Injury
10.13288/j.11-2166/r.2024.22.011
- VernacularTitle:中药药物性急性肾损伤的网络毒理学及免疫机制研究
- Author:
Shuo YANG
1
;
Xiangjia LUAN
2
;
Lianxin WANG
1
Author Information
1. Institute of Basic Research in Clinical Medicine，China Academy of Chinese Medical Science，Beijing，100700
2. Guang'anmen Hospital，China Academy of Chinese Medical Science
- Publication Type:Journal Article
- Keywords:
drug-induced acute kidney injury;
Chinese herbal medicine;
network toxicology;
immunoinfiltration analysis;
Mendelian randomization
- From:
Journal of Traditional Chinese Medicine
2024;65(22):2347-2357
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo 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. MethodsUsing 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. ResultsThere 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 apoptotic signalling pathways， angiogenesis， hypoxia and oxidative stress， and angiogenesis. 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. ConclusionNetwork 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， alongside 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.
