Liu Bingran, Deng Jiankun, Jie Xina, Lu Fuhua, Liu Xusheng, Zhang Difei
The Second Clinical College of Guangzhou University of Chinese Medicine, No.111 Dade Road, Guangzhou, 510405, China.
The Second Clinical College of Guangzhou University of Chinese Medicine, No.111 Dade Road, Guangzhou, 510405, China; Department of Endocrine and Metabolic Diseases, SHANTOU Central Hospital, Shantou, Guangdong, 515031, China.
J Ethnopharmacol. 2022 Jul 15;293:115242. doi: 10.1016/j.jep.2022.115242. Epub 2022 Mar 31.
The Bupi Yishen Formula (BYF) is a patented Chinese herbal compound that has been long used to treat chronic kidney disease (CKD) in the clinic. However, its main active ingredients and underlying mechanisms remain to be elucidated.
Identify the major active ingredients of BYF and investigate its protective effects and specific molecular mechanisms in renal fibrosis.
First, we performed network pharmacology analysis combined with molecular docking to predict the main active compounds, potential therapeutic targets, and intervention pathways that might exert the anti-fibrotic effect of BYF in the kidney. Then, we validated the predictions in both adenine-induced CKD rats and TGFβ1-induced HK-2 cells.
A total of 233 common targets, 25 core targets, and 10 main active compounds from BYF were selected by network pharmacology analyses. Then, GO and KEGG functional enrichment analyses indicated that the renoprotection conferred by BYF against renal fibrosis was mainly associated with the PI3K/AKT signaling. Besides, the molecular docking showed that the 10 main active compounds of BYF were closely docked with three main PI3K/AKT pathway proteins. During the experimental validations, BYF improved renal impairment and alleviated fibrosis by inhibiting the PI3K/AKT signaling activity in the kidney of adenine-induced CKD model rats. Moreover, increased PI3K/AKT signaling activation was associated with fibrotic phenotype changes in adenine-induced CKD rats and TGFβ1-induced HK-2 cells. On the other hand, BYF treatment reduced PI3K/AKT signaling activation and decreased renal fibrogenesis in a dose-dependent manner, thereby indicating that PI3K/AKT signaling was essential for BYF to exert its anti-fibrotic effects. Finally, the inhibitory effect of BYF on renal fibrogenesis was not enhanced while blocking the PI3K/AKT pathway with a broad spectrum PI3K inhibitor (LY294002).
In the present study, we applied a comprehensive strategy based on systemic pharmacology to reveal the anti-fibrotic mechanisms of BYF, at least partially, through the inhibition of PI3K/AKT signaling activation. We also identified BYF as a potential therapeutic agent for renal fibrosis and CKD progression.
补芪益肾方（BYF）是一种已获专利的中药复方，长期以来一直在临床上用于治疗慢性肾脏病（CKD）。然而，其主要活性成分和潜在机制仍有待阐明。
确定BYF的主要活性成分，并研究其在肾纤维化中的保护作用及具体分子机制。
首先，我们进行了网络药理学分析并结合分子对接，以预测可能发挥BYF肾脏抗纤维化作用的主要活性化合物、潜在治疗靶点和干预途径。然后，我们在腺嘌呤诱导的CKD大鼠和TGFβ1诱导的HK-2细胞中验证了这些预测。
通过网络药理学分析，共筛选出BYF的233个共同靶点、25个核心靶点和10种主要活性化合物。然后，基因本体（GO）和京都基因与基因组百科全书（KEGG）功能富集分析表明，BYF对肾纤维化的肾脏保护作用主要与PI3K/AKT信号通路有关。此外，分子对接显示，BYF的10种主要活性化合物与PI3K/AKT信号通路的三种主要蛋白质紧密对接。在实验验证过程中，BYF通过抑制腺嘌呤诱导的CKD模型大鼠肾脏中的PI3K/AKT信号活性，改善了肾功能损害并减轻了纤维化。此外，PI3K/AKT信号激活增加与腺嘌呤诱导的CKD大鼠和TGFβ1诱导的HK-2细胞中的纤维化表型变化有关。另一方面，BYF治疗以剂量依赖的方式降低了PI3K/AKT信号激活并减少了肾脏纤维化，从而表明PI3K/AKT信号通路对于BYF发挥其抗纤维化作用至关重要。最后，在用广谱PI3K抑制剂（LY294002）阻断PI3K/AKT通路时，BYF对肾脏纤维化的抑制作用并未增强。
在本研究中，我们应用了基于系统药理学的综合策略，至少部分地通过抑制PI3K/AKT信号激活来揭示BYF的抗纤维化机制。我们还确定BYF是肾纤维化和CKD进展的潜在治疗药物。
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