基于网络药理学探讨非奈利酮治疗糖尿病肾脏疾病的作用机制

Study on the mechanism of Finerenone in the treatment of diabetic kidney disease based on network pharmacology

目的基于网络药理学探讨新一代非甾体类盐皮质激素受体拮抗剂非奈利酮治疗DKD的作用机制。方法中日友好医院肾病科通过Chemical Book平台、SwissTargetPrediction服务器获取非奈利酮基本信息和作用靶点,使用GeneCards和CTD数据库筛选DKD靶点,相关平台及数据库数据更新截止于2022年9月。构建蛋白质-蛋白质相互作用(PPI)网络。对共同靶点进行基因本体(GO)及京都基因与基因组百科全书(KEGG)富集分析。结果共获取非奈利酮作用靶点104个,DKD靶点6753个,交集靶点83个,PPI网络核心靶点41个。GO富集分析共获取962个富集结果,其中生物过程主要涉及蛋白质磷酸化及自磷酸化、跨膜受体蛋白酪氨酸激酶信号通路等,细胞组成主要涉及细胞周期蛋白依赖性蛋白激酶全酶复合体、膜筏、膜微域等,分子功能主要涉及蛋白激酶活性、以醇为受体的磷酸转移酶活性、内肽酶活性等;KEGG富集分析共获取148条信号通路,主要涉及癌症通路、磷脂酰肌醇3激酶/蛋白激酶B信号通路、松弛素信号通路等。结论非奈利酮可通过多靶点与多通路治疗DKD。

Objective To explore the mechanism of a new generation of non-steroidal glucocorticoid receptor blocker finerenone in the treatment of diabetic kidney disease(DKD)based on network pharmacology.Methods The basic information and targets of finerenone were obtained from Chemical Book and SwissTarget Prediction database,while DKD-related targets were obtained from GeneCards and CTD database by investigators from Department of Nephrology,China-Japan Friendship Hospital.The data from theses platforms and databases was updated in September 2022.The protein-protein interaction(PPI)network was established.Gene Ontology(GO)enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of the common targets were conducted.Results A total of 104targets of finerenone and 6753 targets of DKD were obtained.There were 83 targets with intersection.A total of 41 key targets were obtained by PPI network.GO enrichment analysis was carried out and 962 results were obtained,among which the biological progress(BP)was mainly involved in proteinphosphorylation and autophosphorylation,transmembrane receptor protein tyrosine kinase signal pathway,etc.Cellular Components(CC)was mainly involved in cyclin-dependent protein kinase holoenzyme complex,membrane raft,membrane microdomain,etc.Molecular function(MF)was mainly involved in protein kinase activity,alcohol receptor phosphotransferase activity,endopeptidase activity,etc.Based on the enrichment analysis of KEGG,148 signaling pathways were obtained,including pathways in cancer,PI3K-Akt signaling pathway,Relaxin signaling pathway,etc.Conclusion Finerenone can treat DKD through multi-target and multipathway treatment.