基于网络药理学分析加味参芪地黄汤治疗慢性肾脏病基础上急性肾损伤的潜在机制

Potential Mechanisms of Jiaweishenqidihuangtang in Treating Acute Kidney Injury on Chronic Kidney Disease Based on Network Pharmacology Analysis

摘要: 目的：加味参芪地黄汤为张佩青教授治疗慢性肾脏病的经验用方，现发现对于慢性肾脏病基础上急性肾损伤后肾功能的恢复具有一定疗效，本文通过网络药理学的方法旨在发现加味参芪地黄汤治疗慢性肾脏病基础上急性肾损伤的分子机制。方法：通过中药系统药理学数据库与分析平台(TCMSP)获取党参、黄芪、熟地黄、山茱萸、山药、茯苓、泽泻、牡丹皮、土茯苓、薏苡仁有效成分。利用Swiss Target Prediction分子预测平台预测中药有效成分的作用靶点，通过OMIM，Genecards相关人类疾病数据库分别检索acute kidney injury (AKI)与chronic kidney disease (CKD)，将检索的两种疾病的相关靶点取交集为关键影响靶点。将中药预测的作用靶点与两种疾病的交集靶点取交集为药物对于慢性肾脏病基础上急性肾损伤过程的中药分子靶点。利用STRING数据库与Cytoscape 3.7.2 software构建PPI网络，及中药靶点疾病网络图，并对交集的作用靶点进行KEGG、GO富集分析，预测其具体的作用的机制。结果：筛选中药有效成分140个，药物靶点909个，疾病过程靶点4280个，药物–疾病关键靶点432个，GO富集分析(P < 0.05)中生物过程主要为激酶活性的正调控，肽酰酪氨酸磷酸化，肽酰酪氨酸修饰等；细胞成分主要为膜筏，膜微域，焦黏连筏等；分子功能主要为跨膜受体蛋白酪氨酸激酶活性，蛋白酪氨酸激酶活性，跨膜受体蛋白激酶活性。KEGG富集分析(P < 0.05)包括198条相关通路，通过影响作用的大小筛选出MAPK信号传导通路，EGFR酪氨酸激酶抑制剂耐药性，PI3K-Akt信号传导通路，cAMP信号传导通路等10条信号通路。并以MAPK信号传导通路的影响作用最为显著。结论：通过网络药理学的手段初步筛选出张佩青教授治疗慢性肾脏病基础上急性肾损伤的分子机制的关键靶点，为后续的科学研究，临床治疗提供理论依据。

Abstract: Objective: Jiaweishenqitangdihuangtang is an empirical formula developed by Professor Zhang Peiqing for treating chronic kidney disease (CKD). Recent findings indicate its efficacy in restoring renal function following acute kidney injury (AKI) in CKD patients. This study employs network pharmacology to elucidate the molecular mechanisms underlying Jiaweishenqidihuangtang’s therapeutic effects in AKI on CKD. Method: The active components Dangshen, Huangqi, Shudihuang, Shanzhuyu, Shanyao, Fuling, Zexie, Mudanpi, Tufuling and Yiyiren were obtained through the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP). Using the Swiss Target Prediction molecular prediction platform to forecast the action targets of active components in traditional Chinese medicine, we retrieved acute kidney injury (AKI) and chronic kidney disease (CKD) from the OMIM and GeneCards human disease databases, respectively. The target proteins associated with both diseases were intersected to identify key impact targets. Identify the molecular targets of traditional Chinese medicine for acute kidney injury occurring on the basis of chronic kidney disease by intersecting the predicted target sites of traditional Chinese medicine with the common target sites of both diseases. Constructed protein-protein interaction (PPI) networks and disease-target networks for traditional Chinese medicine using the STRING database and Cytoscape 3.7.2 software. Performed KEGG and GO enrichment analyses on the overlapping functional targets to predict their specific mechanisms of action. Results: Screening identified 140 active components from traditional Chinese medicine, 909 drug targets, 4280 disease process targets, and 432 key drug-disease targets. In GO enrichment analysis (P < 0.05), the predominant biological processes were: positive regulation of kinase activity, peptidyl-tyrosine phosphorylation, peptidyl-tyrosine modification etc.; CC: membrane raft, membrane microdomain, focal adhesion etc.; MF: transmembrane receptor protein tyrosine kinase activity, protein tyrosine kinase activity, transmembrane receptor protein kinase activity etc. KEGG enrichment analysis (P < 0.05) identified 198 relevant pathways. After screening based on the magnitude of influence, 10 signaling pathways were selected: the MAPK signaling pathway, EGFR tyrosine kinase inhibitor resistance, the PI3K-Akt signaling pathway, the cAMP signaling pathway, and others. Among these, the MAPK signaling pathway exhibited the most significant influence. Conclusion: Using network pharmacology approaches, we have preliminarily identified key targets in the molecular mechanism underlying Professor Zhang Peiqing’s treatment of acute kidney injury superimposed on chronic kidney disease. This provides a theoretical basis for subsequent scientific research and clinical treatment.