2023 年第 12 期 第 18 卷

基于网络药理学预测水蛭素干预血瘀证治疗IgA肾病的通路和靶点

Prediction of pathways and targets of hirudin in the treatment of IgA nephropathy with blood stasis syndrome based on network pharmacology

作者：刘鑫1谢永祥1刘前程2肖阳平2梁丽2孟立锋1

英文作者：Liu Xin1 Xie Yongxiang1 Liu Qiancheng2 Xiao Yangping2 Liang Li2 Meng Lifeng1

单位：1广西中医药大学第一附属医院肾病内科，南宁530023；2广西中医药大学，南宁530023

英文单位：1Department of Nephrology the First Affiliated Hospital of Guangxi University of Chinese Medicine Nanning 530023 China; 2Guangxi University of Chinese Medicine Nanning 530023 China

关键词：水蛭素；血瘀证；IgA肾病；网络药理学

英文关键词：Hirudin;Bloodstasissyndrome;IgAnephropathy;Networkpharmacology

• 摘要：

• 目的  基于网络药理学方法探讨水蛭素通过干预血瘀证治疗IgA肾病（IgAN）的通路及靶点。方法  通过SuperPred与PALM-IST数据库获取水蛭素潜在靶点，使用Genecards和OMIM获取血瘀证与IgAN的相关靶点。将水蛭素和血瘀证的交集靶点导入String数据库构建蛋白质-蛋白质相互作用网络并进行拓扑学分析，以度值排序前10节点为血瘀证相关的水蛭素核心靶点。在Nephroseq数据库中分析水蛭素核心靶点与IgAN患者临床特征的相关性。结果  水蛭素的204个靶点中有41个靶点与血瘀证（1 047个靶点）相关，其中核心靶点为血管内皮生长因子A（VEGFA）、血管性血友病因子、丝氨酸蛋白酶抑制因子肽酶抑制因子、前列腺素内过氧化物合酶、凝血因子Ⅲ、凝血因子Ⅱ（F2）、热休克蛋白90α家族A类成员1（HSP90AA1）、低氧诱导因子1（HIF1A）、基质金属蛋白酶2（MMP2）和雌激素受体1（ESR1）。相关性分析结果表明，IgAN患者肾小球中VEGFA、ESR1 mRNA表达与肾小球滤过滤（GFR）呈正相关，HIF1A mRNA表达与GFR呈负相关（均P＜0.05）；肾小管间质中VEGFA mRNA表达与血肌酐呈负相关，HIF1A mRNA表达与血肌酐呈正相关（均P＜0.05）；血液中HSP90AA1 mRNA表达与血肌酐呈负相关（P=0.006）；肾小管中MMP2 mRNA表达与血肌酐呈正相关（P=0.002）；血液中F2 mRNA表达与24 h尿蛋白量呈负相关，肾小管间质中ESR1 mRNA表达与24 h尿蛋白量呈负相关（均P＜0.05）。结论  VEGFA、F2、HIF1A、HSP90AA1、MMP2和ESR1是水蛭素干预血瘀证治疗IgAN的关键基因且与临床特征密切相关。

• Objective To explore the pathways and targets of hirudin (HIR) in the treatment of IgA nephropathy through the intervention of blood stasis syndrome. Methods The potential targets of HIR were obtained by SuperPred and PALM-IST database, and the related targets of blood stasis syndrome and IgA nephropathy were obtained by Genecards and OMIM. The intersection targets of HIR and blood-stasis syndrome were imported into String database to construct protein-protein interactions network and topological analysis was conducted. The top 10 nodes ranked by degree value were the core targets of HIR related to blood-stasis syndrome. Correlation between HIR core targets and clinical characteristics was analyzed in Nephroseq database. Results  Among 204 targets of HIR, 41 were associated with blood stasis syndrome (1 047 targets), among which the core targets were vascular endothelial growth factor A (VEGFA), von Willebrand factor, serpin family E member 1, prostaglandin-endoperoxide synthase 2, coagulation factor Ⅲ, coagulation factor Ⅱ (F2), heat shot protein 90 AA1 (HSP90AA1), hypoxia inducible factor 1 subunit alpha (HIF1A), matrix metallopeptidase 2 (MMP2) and estrogen receptors 1 (ESR1). Correlation analysis showed that VEGFA and ESR1 mRNA expressions were positively correlated with glomerular filtration rate (GFR), and HIF1A mRNA expression was negatively correlated with GFR in glomerular of IgA nephropathy patients (all P<0.05). In tubulointerstitium, VEGFA mRNA expression was negatively correlated with serum creatinine and HIF1A mRNA expression was positively correlated with serum creatinine (both P<0.05). HSP90AA1 mRNA expression in serum was negatively correlated with serum creatinine (P=0.006). MMP2 mRNA expression in renal tubule was positively correlated with serum creatinine （P=0.002）. F2 mRNA expression in serum was negatively correlated with 24 h urine protein, and ESR1 mRNA expression in tubulointerstitium was negatively correlated with 24 h urine protein (both P<0.05). Conclusion VEGFA, F2, HIF1A, HSP90AA1, MMP2 and ESR1 are the key genes of HIR intervention in the treatment of IgA nephropathy with blood stasis syndrome and are closely related to clinical characteristics.