基于网络药理学探究布地奈德治疗IgA肾病的作用机制

doi:10.12114/j.issn.1007-9572.2023.0299

中国全科医学 ›› 2023, Vol. 26 ›› Issue (35): 4453-4458.DOI: 10.12114/j.issn.1007-9572.2023.0299

基于网络药理学探究布地奈德治疗IgA肾病的作用机制

张康¹, 赵婷婷², 张波², 高梦琦³, 李昱熹², 王邵鹏⁴, 赵文景¹^,^*()

1．100010　北京市，首都医科大学附属北京中医医院肾病科
2．100029　北京市，中日友好临床医学研究所
3．100102　北京市，中国中医科学院望京医院肾病内分泌科
4．261053　山东省潍坊市，潍坊医学院药学院

收稿日期:2023-03-24 修回日期:2023-07-10 出版日期:2023-12-15 发布日期:2023-07-28
通讯作者: 赵文景
作者贡献：张康设计文章的思路与框架，绘制图表，撰写论文初稿；张波、高梦琦进行文献收集、整理和提炼；李昱熹、王邵鹏进行论文的修订；赵婷婷、赵文景负责论文终稿的审定，文章的质量控制及审校；张康、赵文景对文章整体负责，监督管理。
基金资助:
首都卫生发展科研专项项目(2020-3-2235)

Study on the Mechanism of Budesonide in the Treatment of IgA Nephropathy Based on Network Pharmacology

ZHANG Kang¹, ZHAO Tingting², ZHANG Bo², GAO Mengqi³, LI Yuxi², WANG Shaopeng⁴, ZHAO Wenjing¹^,^*()

1. Department of Nephrology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
2. Institute of Clinical Medicine, China-Japan Friendship Hospital, Beijing 100029, China
3. Department of Nephrology and Endocrinology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
4. College of Pharmacy, Weifang Medical University, Weifang 261053, China

Received:2023-03-24 Revised:2023-07-10 Published:2023-12-15 Online:2023-07-28
Contact: ZHAO Wenjing

分享到

摘要/Abstract

摘要： 背景 IgA肾病是我国及世界范围最常见的原发性肾小球肾炎，25%~30%的患者在确诊后20年内会进展至终末期肾病。目前尚无针对IgA肾病有效且安全的治疗方案。近年来针对IgA肾病治疗的新药研究进展迅速，其中靶向迟释布地奈德胶囊是全球首个IgA肾病对因治疗药物。目的基于网络药理学探究皮质类固醇布地奈德肠溶胶囊治疗IgA肾病的作用机制。方法通过Chemical Book平台筛选布地奈德的作用靶点；并利用GeneCards和CTD数据库获取IgA肾病的相关靶点。通过韦恩图取交集获得布地奈德-IgAN共同靶点。构建蛋白质-蛋白质相互作用（PPI）网络图，对交集靶点进行基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析。结果筛选出布地奈德作用靶点242个，IgA肾病候选靶点1 443个，交集靶点146个。PPI网络核心靶点15个：白介素6（IL-6）、肿瘤坏死因子（TNF）、白介素10（IL-10）、血管内皮生长因子A（VEGFA）、表皮生长因子受体（EGFR）、白介素1B（IL-1B）、白介素4（IL-4）、白介素8（CXCL8）、1号染色体的基因（JUN）、白介素13（IL-13）、白介素2（IL-2）、趋化因子2（CCL2）、TOLL样受体4（TLR4）、集落刺激因子2（CSF2）、白蛋白（ALB）。富集分析共获得1 646个GO富集结果，174条KEGG信号通路，其中生物过程（BP）主要涉及磷酸化的正向调节、炎症反应、细胞运动的正向调节等，细胞组成（CC）主要涉及细胞质囊泡腔、囊腔、分泌颗粒腔等，分子过程（MF）主要涉及信号受体激活活性、信号受体调节活性、受体配体活性等。KEGG信号通路主要涉及白介素17信号通路、细胞因子-细胞因子受体相互作用、癌症中的通路、肿瘤坏死因子信号通路等。结论本研究初步验证布地奈德可通过IL-6、TNF、IL-10、VEGFA、EGFR等靶点作用于细胞因子-细胞因子受体相互作用通路、白介素17信号通路、癌症中的通路、肿瘤坏死因子信号通路等多条信号通路治疗IgA肾病，为布地奈德的进一步研究及临床实践提供理论依据。

关键词: 布地奈德, 肾小球肾炎, IgA, IgA肾病, 网络药理学, 信号通路

Abstract:

Background

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in China and worldwide, approximately 25%-30% of patients will progress to end-stage renal disease within 20 years after diagnosis. Currently, there is no effective and safe treatment specifically for IgAN. In recent years, there has been a rapid progress in the research of new drugs for IgAN, among which the targeted delayed-release budesonide capsules is the first allopathic drug for IgAN globally.

Objective

To investigate the mechanism of corticosteroid budesonide capsules in the treatment of IgAN based on network pharmacology.

Methods

Chemical Book platform was used to screen the targets of budesonide; GeneCards and CTD databases were utilized to obtain the relevant targets of IgAN. The intersection of budesonide targets and IgAN targets was obtained through a Venn diagram. A protein-protein interaction (PPI) network map was constructed, and gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed on the intersecting targets.

Results

A total of 242 targets for budesonide, 1 443 candidate targets for IgAN, and 146 intersecting targets were selected. The 15 core targets in the PPI network included interleukin-6 (IL-6), tumor necrosis factor (TNF), interleukin-10 (IL-10), vascular endothelial growth factor A (VEGFA), epidermal growth factor receptor (EGFR), interleukin-1B (IL-1B), interleukin-4 (IL-4), interleukin-8 (CXCL8), gene on chromosome 1 (JUN), interleukin-13 (IL-13), interleukin-2 (IL-2), chemokine 2 (CCL2), toll-like receptor 4 (TLR4), colony-stimulating factors (CSF2), and albumin (ALB). Enrichment analysis revealed 1 646 GO enrichment results and 174 KEGG signaling pathways. The biological processes (BP) mainly involved positive regulation of phosphorylation, inflammatory response, and positive regulation of cell movement. The cellular components (CC) mainly involved cytoplasmic vesicle lumen, cyst cavity, and secretory granule lumen. The molecular functions (MF) mainly involved receptor signaling activity, receptor regulator activity, and receptor ligand activity. The KEGG signaling pathways mainly included interleukin 17 signaling pathway, cytokine-cytokine receptor interaction, pathways in cancer, and tumor necrosis factor signaling pathway.

Conclusion

This study provides preliminary verified that budesonide can treat IgAN by targeting IL-6, TNF, IL-10, VEGFA, EGFR, and other targets, through multiple signaling pathways, like cytokine-cytokine receptor interaction, interleukin-17 signaling pathway, pathways in cancer, and tumor necrosis factor signaling pathway, providing a theoretical basis for further research and clinical practice of budesonide.

Key words: Budesonide, Glomerulonephritis, IgA, IgA nephropathy, Network pharmacology, Signaling pathway

张康,赵婷婷,张波,等. 基于网络药理学探究布地奈德治疗IgA肾病的作用机制[J]. 中国全科医学, 2023, 26(35): 4453-4458. DOI: 10.12114/j.issn.1007-9572.2023.0299.
ZHANG Kang,ZHAO Tingting,ZHANG Bo, et al. Study on the Mechanism of Budesonide in the Treatment of IgA Nephropathy Based on Network Pharmacology[J]. Chinese General Practice, 2023, 26(35): 4453-4458. DOI: 10.12114/j.issn.1007-9572.2023.0299.

图/表 10

图1 布地奈德基本信息

Figure 1 Basic information of budesonide

图2 布地奈德-IgAN共同靶点韦恩图

Figure 2 Venn diagram of the intersection of budesonide and IgA nephropathy targets

图3 布地奈德-IgAN靶基因网络

Figure 3 Budesonide-IgAN target genes network

图4 布地奈德-IgAN交集靶点的PPI网络图

Figure 4 PPI network map of the intersection of budesonide and IgAN targets

图5 15个关键靶基因注：IL-6=白介素6，TNF=肿瘤坏死因子，IL-1B=白介素1B，IL-10=白介素10，VEGFA=血管内皮生长因子A，IL-4=白介素4，CXCL8=白介素8，EGFR=表皮生长因子受体，JUN=1号染色体的基因，IL-13=白介素13，IL-2=白介素2，CCL2=趋化因子2，TLR4=TOLL样受体4，CSF2=集落刺激因子2，ALB=白蛋白。

Figure 5 15 core target genes

表1 PPI网络15个关键靶基因及其拓扑参数

Table 1 15 core target genes of PPI network and their topological parameters

靶点	度中心性	介值中心性	接近中心性
IL-6	67	1 621.375	0.640 777
TNF	63	1 648.284	0.62 857 145
IL-1B	57	1 289.359	0.6 055 046
IL-10	50	612.046 9	0.5 689 655
VEGFA	43	501.654 1	0.559 322
IL-4	43	532.723 1	0.545 455
CXCL8	41	353.113 2	0.538 776
EGFR	41	844.235 5	0.55
JUN	39	865.605 5	0.540 984
IL-13	39	611.600 8	0.517 647
IL-2	37	372.990 9	0.513 619
CCL2	37	242.563 8	0.532 258
TLR4	36	736.172 1	0.517 647
CSF2	35	131.414 7	0.507 692
ALB	34	1 397.614	0.545 455

图6 布地奈德治疗IgAN关键靶点的GO-BP富集分析

Figure 6 GO-BP enrichment analysis of core targets of IgAN treated with budesonide

图7 布地奈德治疗IgAN关键靶点的GO-CC富集分析

Figure 7 GO-CC enrichment analysis of core targets of IgAN treated with budesonide

图8 布地奈德治疗IgAN关键靶点的GO-MF富集分析

Figure 8 GO-MF enrichment analysis of core targets of IgAN treated with budesonide

图9 布地奈德治疗IgAN关键信号通路

Figure 9 Key signaling pathways of IgAN treated with budesonide

参考文献 28

[1]	SCHENA F P，NISTOR I. Epidemiology of IgA nephropathy：a global perspective[J]. Semin Nephrol，2018，38（5）：435-442. DOI：10.1016/j.semnephrol.2018.05.013.
[2]	HOU J H，ZHU H X，ZHOU M L，et al. Changes in the spectrum of kidney diseases：an analysis of 40，759 biopsy-proven cases from 2003 to 2014 in China[J]. Kidney Dis，2018，4（1）：10-19. DOI：10.1159/000484717.
[3]	RODRIGUES J C，HAAS M，REICH H N. IgA nephropathy[J]. Clin J Am Soc Nephrol，2017，12（4）：677-686. DOI：10.2215/cjn.07420716.
[4]	Kidney Disease：Improving Global Outcomes （KDIGO） Glomerular Diseases Work Group. KDIGO 2021 clinical practice guideline for the management of glomerular diseases[J]. Kidney Int，2021，100（4S）：S1-276. DOI：10.1016/j.kint.2021.05.021.
[5]	RAUEN T，EITNER F，FITZNER C，et al. Intensive supportive care plus immunosuppression in IgA nephropathy[J]. N Engl J Med，2015，373（23）：2225-2236. DOI：10.1056/NEJMoa1415463.
[6]	LV J C，ZHANG H，WONG M G，et al. Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy：the TESTING randomized clinical trial[J]. JAMA，2017，318（5）：432-442. DOI：10.1001/jama.2017.9362.
[7]	BARRATT J，LAFAYETTE R，KRISTENSEN J，et al. Results from part A of the multi-center，double-blind，randomized，placebo-controlled NefIgArd trial，which evaluated targeted-release formulation of budesonide for the treatment of primary immunoglobulin A nephropathy[J]. Kidney Int，2023，103（2）：391-402. DOI：10.1016/j.kint.2022.09.017.
[8]	MAKITA Y，SUZUKI H，NAKANO D，et al. Glomerular deposition of galactose-deficient IgA1-containing immune complexes via glomerular endothelial cell injuries[J]. Nephrol Dial Transplant，2022，37（9）：1629-1636. DOI：10.1093/ndt/gfac204.
[9]	HE J W，ZHOU X J，LV J C，et al. Perspectives on how mucosal immune responses，infections and gut microbiome shape IgA nephropathy and future therapies[J]. Theranostics，2020，10（25）：11462-11478. DOI：10.7150/thno.49778.
[10]	BARRATT J，ROVIN B H，CATTRAN D，et al. Why target the gut to treat IgA nephropathy?[J]. Kidney Int Rep，2020，5（10）：1620-1624. DOI：10.1016/j.ekir.2020.08.009.
[11]	BOYD J K，CHEUNG C K，MOLYNEUX K，et al. An update on the pathogenesis and treatment of IgA nephropathy[J]. Kidney Int，2012，81（9）：833-843. DOI：10.1038/ki.2011.501.
[12]	TANG Y Y，ZHU Y F，HE H D，et al. Gut dysbiosis and intestinal barrier dysfunction promotes IgA nephropathy by increasing the production of Gd-IgA1[J]. Front Med，2022，9：944027. DOI：10.3389/fmed.2022.944027.
[13]	HOU J，ZHANG L，WU H，et al. Increased Tim-3+ monocytes/macrophages are associated with disease severity in patients with IgA nephropathy[J]. Int Immunopharmacol，2021，97：107666. DOI：10.1016/j.intimp.2021.107666.
[14]	GROZA Y，JEMELKOVA J，KAFKOVA L R，et al. IL-6 and its role in IgA nephropathy development[J]. Cytokine Growth Factor Rev，2022，66：1-14. DOI：10.1016/j.cytogfr.2022.04.001.
[15]	MAKITA Y，SUZUKI H，KANO T，et al. TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy[J]. Kidney Int，2020，97（2）：340-349. DOI：10.1016/j.kint.2019.08.022.
[16]	程劲，徐萍萍，王巍巍，等. 尿液中IL-6、KIM-1、TGF-β1水平与IgA肾病患者肾脏病理及临床指标的相关性[J]. 中国中西医结合肾病杂志，2017，18（5）：433-435.
[17]	LEUNG J C K，LAI K N，TANG S C W. Role of mesangial-podocytic-tubular cross-talk in IgA nephropathy[J]. Semin Nephrol，2018，38（5）：485-495. DOI：10.1016/j.semnephrol.2018.05.018.
[18]	WAN Q，ZHOU J B，WU Y S，et al. TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy[J]. Ren Fail，2022，44（1）：1216-1226. DOI：10.1080/0886022X.2022.2079527.
[19]	MYLLYMÄKI J M，HONKANEN T T，SYRJÄNEN J T，et al. Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy[J]. Kidney Int，2007，71（4）：343-348. DOI：10.1038/sj.ki.5002046.
[20]	ROMAGNANI S. T-cell subsets （Th1 versus Th2）[J]. Ann Allergy Asthma Immunol，2000，85（1）：9-18；quiz18，21. DOI：10.1016/S1081-1206(10)62426-X.
[21]	GAO J，WEI L T，FU R G，et al. Association of interleukin-10 polymorphisms （rs1800872，rs1800871，and rs1800896） with predisposition to IgA nephropathy in a Chinese Han population：a case-control study[J]. Kidney Blood Press Res，2017，42（1）：89-98. DOI：10.1159/000471899.
[22]	BANTIS C，HEERING P J，AKER S，et al. Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis[J]. Kidney Int，2004，66（1）：288-294. DOI：10.1111/j.1523-1755.2004.00730.x.
[23]	GNUDI L，BENEDETTI S，WOOLF A S，et al. Vascular growth factors play critical roles in kidney glomeruli[J]. Clin Sci，2015，129（12）：1225-1236. DOI：10.1042/CS20150403.
[24]	KIKUCHI R，STEVENS M，HARADA K，et al. Anti-angiogenic isoform of vascular endothelial growth factor-a in cardiovascular and renal disease[J]. Adv Clin Chem，2019，88：1-33. DOI：10.1016/bs.acc.2018.10.001.
[25]	FENG S Z，HUANG N Y，XUE M R，et al. Association between urinary VEGFA and renal pathology of IgA nephropathy patients[J]. J Clin Lab Anal，2021，35（10）：e23995. DOI：10.1002/jcla.23995.
[26]	宋坚，王旭东，刘宏斌，等. 肾安方对慢性肾脏病大鼠EGFR介导的PI3K/Akt通路的影响[J]. 中医药导报，2022，28（8）：22-26. DOI：10.13862/j.cn43-1446/r.2022.08.005.
[27]	KHAN A，ALI A，JUNAID M，et al. Identification of novel drug targets for diamond-blackfan anemia based on RPS19 gene mutation using protein-protein interaction network[J]. BMC Syst Biol，2018，12（Suppl 4）：39. DOI：10.1186/s12918-018-0563-0.
[28]	黄海，列才华，梁兰青，等. 细胞因子对IgA肾病患者IgA1 O-糖基化的影响及相关机制研究[J]. 东南国防医药，2019，21（1）：44-48. DOI：10.3969/j.issn.1672-271X.2019.01.010.

基于网络药理学探究布地奈德治疗IgA肾病的作用机制

Study on the Mechanism of Budesonide in the Treatment of IgA Nephropathy Based on Network Pharmacology

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 10

参考文献 28

相关文章 15

编辑推荐

Metrics

留言

[1]	周文京, 赏石丽, 杨倩, 冯悦荣, 李俊. 血小板/白蛋白比值与免疫球蛋白A肾病临床和病理特征的相关性研究[J]. 中国全科医学, 2023, 26(29): 3657-3664.
[2]	孙帅刚, 盛晓笑, 张文惠, 田慧娟, 翟亚玲. 免疫球蛋白G4合并其他不同免疫球蛋白G亚型沉积的特发性膜性肾病患者的临床病理及短期预后分析[J]. 中国全科医学, 2023, 26(21): 2632-2638.
[3]	朱丹萌, 黄玉莹, 罗统安, 贺长源, 陈日兰. 刺血疗法结合壮医药线点灸对急性痛风性关节炎大鼠TLRs/MyD88信号通路的影响[J]. 中国全科医学, 2023, 26(20): 2525-2531.
[4]	鄢鹏, 宋健玲, 房向东. 甲状旁腺激素1型受体在肾脏疾病中的研究进展[J]. 中国全科医学, 2023, 26(11): 1398-1403.
[5]	中华中医药学会肾病分会, 广东省中医药学会肾病专业委员会, 杨丽虹, 苏佩玲, 包崑. 特发性膜性肾病中医临床实践指南（2021）[J]. 中国全科医学, 2023, 26(06): 647-659.
[6]	郭栋伟, 张鹏飞, 任明君, 廖丽君, 黄茹妍, 罗湘蓉. 银杏叶提取物防治慢性阻塞性肺疾病的机制研究：基于PI3K/Akt/mTOR信号通路调控肺泡巨噬细胞自噬[J]. 中国全科医学, 2023, 26(03): 293-303.
[7]	柯江华, 段姝伟, 刘林昌, 李爽, 柯雨景, 曲逸伦, 姚进, 陈香美. 伴恶性高血压的原发性IgA肾病临床、病理及中医证候特征研究[J]. 中国全科医学, 2022, 25(27): 3395-3403.
[8]	叶坤, 雷敏, 谢欣, 郑晖, 陈敏, 余曙光. 基于网络药理学与分子对接技术探讨黄芪建中汤治疗腹泻型肠易激综合征的作用机制研究[J]. 中国全科医学, 2022, 25(15): 1814-1824.
[9]	王孟迪, 杜悦. 细胞因子变化是否与IgA血管炎患儿肾损害相关？[J]. 中国全科医学, 2022, 25(08): 973-978.
[10]	衡立, 张立国, 董婧婷, 李治国, 曹凤宏. 氧化应激介导雄激素受体信号重激活在前列腺癌演进中的分子机制研究进展[J]. 中国全科医学, 2022, 25(05): 636-642.
[11]	刘童童，王宇阳，杨丽平，冒慧敏，占永立. 不同药物治疗方案干预进展性IgA肾病有效性和安全性的网状Meta分析[J]. 中国全科医学, 2021, 24(8): 989-1000.
[12]	罗萌，高静，段昭远，刘承梅，李瑞青，苏凯奇，陈卓，冯晓东. 基于核因子κB信号通路的中医方药防治认知障碍机制的研究进展[J]. 中国全科医学, 2021, 24(36): 4640-4647.
[13]	韩涛，尹逊路，展嘉文，魏戌，冯敏山，于杰，李学朋，陈明，朱立国. 补肾活血中药介导Wnt/β-catenin信号通路延缓椎间盘终板压力退变的机制研究[J]. 中国全科医学, 2021, 24(35): 4427-4436.
[14]	孙凯，朱立国，魏戌，银河，李秋月，秦晓宽，杨博文. 基于UPLC-Q-TOF-MS/MS结合网络药理学的壮腰通络方延缓腰椎间盘退行性病变的化学成分及作用机制研究[J]. 中国全科医学, 2021, 24(35): 4437-4446.
[15]	鄢泽然，陈光耀，陈嘉琪，徐愿，罗静，陶庆文. 基于Wnt/β-catenin通路探究骨痹通方对软骨基质的保护作用及其机制[J]. 中国全科医学, 2021, 24(24): 3122-3128.