Liu Bingran, Chen Guowei, Mo Haoyu, Liang Xiaolin, Su Xiaoyan, Lu Fuhua, Lin Qizhan, Liu Xusheng, Deng Jiankun, Zhang Difei
State Key Laboratory of Traditional Chinese Medicine Syndrome/Department of Nephrology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, No. 55 Neihuan West Road, Guangzhou, Guangdong 510006, PR China; The Second Clinical College of Guangzhou University of Chinese Medicine, No. 111 Dade Road, Guangzhou, Guangdong 510120, PR China.
The Second Clinical College of Guangzhou University of Chinese Medicine, No. 111 Dade Road, Guangzhou, Guangdong 510120, PR China.
Phytomedicine. 2025 Jul 3;145:157055. doi: 10.1016/j.phymed.2025.157055.
Bupi Yishen formula (BYF) is a traditional Chinese herbal mixture with proven efficacy in attenuating kidney function deterioration among patients with advanced chronic kidney disease (CKD), and improving renal fibrosis of CKD animal models. Previous studies have shown that BYF rehabilitates metabolic dysregulation under CKD condition, but its exact mechanism remains unclear.
This study aimed to elucidate the therapeutic effect and its potential mechanism on regulating renal energy metabolism in CKD.
An adenine-induced CKD rat model was treated with two doses of BYF decoction (15 g/kg/day or 30 g/kg/day) and losartan (as the positive control) for 4 weeks. Lipidomic and transcriptomic analyses of kidney samples from CKD rats revealed the BYF-reversed different lipid species and gene expression profiles respectively, thereby identifying potential pharmacological mechanisms. Further in vivo and in vitro experiments, network analyses, and molecular docking was used to confirm the proposed mechanisms affected by BYF.
BYF had a profound impact on alleviating renal impairment and profibrotic phenotypes in CKD rats. Lipid profiling of kidneys from CKD rats showed that the dysmetabolism of glycerophospholipids, sphingolipids, and glycerolipids was primarily influenced by BYF. Transcriptome analysis of CKD rats identified renal energy metabolism (including fatty acid oxidation [FAO], glucose metabolism) and mitochondrial oxidative phosphorylation (OXPHOS) as the key dysregulated pathways, which were reversed by BYF. Further experiments confirmed that BYF partially restored defective FAO, dysregulated glucose metabolism, and impaired mitochondrial OXPHOS in the kidneys of CKD rats and TGFβ1-induced human tubule HK-2 cells. Besides, network analyses combined with molecular docking demonstrated a strong binding effect of BYF's core compounds on key targets related to energy metabolism.
These results suggest that BYF protects against CKD by restoring renal energy homeostasis and mitochondrial OXPHOS, offering potential as an alternative therapy for renal fibrosis inherent to CKD.
补芪益肾方（BYF）是一种传统的中草药合剂，在延缓晚期慢性肾脏病（CKD）患者肾功能恶化以及改善CKD动物模型肾纤维化方面具有已证实的疗效。既往研究表明，BYF可纠正CKD状态下的代谢失调，但其确切机制仍不清楚。
本研究旨在阐明其对CKD肾能量代谢调节的治疗作用及其潜在机制。
用两剂量的BYF水煎剂（15 g/kg/天或30 g/kg/天）和氯沙坦（作为阳性对照）对腺嘌呤诱导的CKD大鼠模型进行治疗，为期4周。对CKD大鼠肾脏样本进行脂质组学和转录组学分析，分别揭示了BYF逆转的不同脂质种类和基因表达谱，从而确定潜在的药理机制。进一步通过体内和体外实验、网络分析以及分子对接来证实BYF影响的所提出机制。
BYF对减轻CKD大鼠的肾损伤和促纤维化表型有深远影响。CKD大鼠肾脏的脂质谱分析表明，甘油磷脂、鞘脂和甘油酯的代谢失调主要受BYF影响。对CKD大鼠的转录组分析确定肾能量代谢（包括脂肪酸氧化[FAO]、葡萄糖代谢）和线粒体氧化磷酸化（OXPHOS）为关键的失调途径，而这些途径被BYF逆转。进一步实验证实，BYF部分恢复了CKD大鼠肾脏和转化生长因子β1诱导的人肾小管HK - 2细胞中缺陷的FAO、失调的葡萄糖代谢以及受损的线粒体OXPHOS。此外，网络分析结合分子对接证明BYF的核心化合物对与能量代谢相关的关键靶点具有强结合作用。
这些结果表明，BYF通过恢复肾能量稳态和线粒体OXPHOS来预防CKD，为CKD固有肾纤维化提供了一种潜在的替代治疗方法。
