芹菜素通过 PI3K/AKT 和 NF-κB 通路抑制肾小管上皮细胞的上皮间充质转化以治疗肾脏纤维化

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS

ACS Applied Bio Materials Pub Date : 2024-10-28 DOI:10.1016/j.gene.2024.149056

Tao Sun , Baoying Wang , Zhan Wang , Lei Chen , Zhenzhen Li , Ningning Li

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引用次数: 0

摘要

肾脏纤维化是慢性肾脏疾病进展的关键因素。以往的研究表明，芹菜素（API）具有改善肾脏纤维化的潜力，但其治疗机制仍不清楚。本研究旨在利用网络药理学和实验验证阐明芹菜素治疗肾脏纤维化的机制。首先，我们利用中药系统药理学（TCMSP）数据库和GeneCards数据库确定了API的分子靶点和相关基因。接着，我们构建了API-肾脏纤维化靶点网络，然后进行了蛋白-蛋白相互作用（PPI）分析。随后，我们利用注释、可视化和综合发现数据库（DAVID）进行了基因本体（GO）和京都基因和基因组百科全书（KEGG）通路富集等分析。我们还进行了分子对接研究，以探索 API 与关键蛋白的相互作用。为了验证 API 治疗肾脏纤维化的机制，我们使用了由转化生长因子-β1（TGF-β1）诱导的上皮-间质转化（EMT）人肾-2（HK-2）细胞模型。我们发现了77个API靶基因、8434个肾脏纤维化靶基因和64个交叉基因，它们主要富集于核因子卡巴-B（NF-κB）和磷脂酰肌醇3-激酶/蛋白激酶B（PI3K-AKT）通路。原料药通过调节α-平滑肌肌动蛋白（α-SMA）和E-钙粘蛋白的表达，以及抑制与PI3K-AKT和NF-κB通路相关的p-PI3K、p-AKT和p-P65的蛋白表达，明显抑制了TGF-β1诱导的HK-2细胞的EMT。然而，同时服用 PI3K 激动剂 740Y-P 可以抵消原料药对这些蛋白表达的抑制作用。总之，这些发现突出了API通过PI3K-AKT和NF-κB途径调节肾小管上皮细胞EMT从而治疗肾纤维化的潜力。

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Apigenin inhibits epithelial mesenchymal transition in renal tubular epithelial cells through PI3K/AKT and NF-κB pathways for treating renal fibrosis

Renal fibrosis is a crucial factor in the progression of chronic kidney diseases. Previous studies have suggested that apigenin (API) has potential in ameliorating renal fibrosis, but its therapeutic mechanism remains unclear. This study aims to elucidate the mechanisms by which API treats renal fibrosis using network pharmacology and experimental validation. Initially, we used the Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database and GeneCards database to identify molecular targets of API and associated genes. Next, we constructed a network of API-renal fibrosis targets, followed by protein–protein interaction (PPI) analysis. Subsequent analyses, such as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, were performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). We also performed molecular docking studies to explore API’s interactions with key proteins. To validate API’s mechanism in treating renal fibrosis, we used a Human Kidney-2 (HK-2) cell model of epithelial-mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1). We identified 77 API target genes, 8434 renal fibrosis target genes, and 64 intersection genes, which were primarily enriched in nuclear factor kappa-B (NF-κB) and Phosphatidylinositide 3-kinases/protein kinase B (PI3K-AKT) pathways. API significantly inhibited EMT in TGF-β1-induced HK-2 cells by regulating the expression of α-Smooth muscle actin (α-SMA) and E-cadherin and suppressing the protein expression of p-PI3K, p-AKT, and p-P65, which are related to the PI3K-AKT and NF-κB pathways. However, co-administration of the PI3K agonist 740Y-P counteracted API’s inhibitory effects on these protein expressions. In summary, these findings highlight API’s therapeutic potential in treating renal fibrosis by modulating EMT in renal tubular epithelial cells via the PI3K-AKT and NF-κB pathways.

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来源期刊

ACS Applied Bio Materials Chemistry-Chemistry (all)

CiteScore

9.40

自引率

2.10%

发文量

464