Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People's Republic of China.
The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People's Republic of China.
Drug Des Devel Ther. 2024 Sep 14;18:4119-4134. doi: 10.2147/DDDT.S457100. eCollection 2024.
Huangqi-Danshen decoction (HDD) is a Chinese medicinal herb pair with good efficacy in treating chronic kidney disease, but its mechanism needs to be clarified.
To uncover the underlying mechanism of HDD antagonizing renal fibrosis through network pharmacology (NP) analysis and experimental validation.
The chemical components of water extract of HDD were analyzed by combining the ultra-high performance liquid chromatography coupled with Q-Exactive mass spectrum analysis (UHPLC-QE-MS) and HERB database. NP was used to identify core common targets of HDD components and renal fibrosis. Subsequently, male C57BL/6 mice were divided into Sham, unilateral ureteral obstruction (UUO) and UUO+HDD groups. Renal function, histopathology, Western blotting, and immunohistochemistry analyses were used to evaluate the protective effect of HDD on UUO mice. The effects of HDD on signaling pathways were validated in both UUO mice and transforming growth factor-β1 (TGF-β1)-induced HK-2 cells.
By combining UHPLC-QE-MS analysis and HERB database, 25 components were screened in HDD extract. There were 270 intersection targets of the 25 components and renal fibrosis. Based on their scores in protein-protein interaction analysis and degree values in component-pathway-target triadic network, 6 core common targets of the 25 components and renal fibrosis were identified, namely phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription 3 (Stat3), non-receptor tyrosine kinase Src (Src), epidermal growth factor receptor (EGFR), matrix metalloproteinase 9 (MMP9), and MMP2. HDD ameliorated renal tubular damage and collagen deposition and downregulated fibrosis-related proteins expression in UUO mice. Furthermore, HDD was demonstrated to reduce PI3K, Stat3, Src, EGFR, and MMP2 expressions, and enhance MMP9 expression in the kidney of UUO mice and in TGF-β1-induced HK-2 cells.
HDD can alleviate renal fibrosis which may be related to regulating the expression of essential proteins in the epithelial-mesenchymal transition and extracellular matrix production/degradation signaling pathways.
黄芪-丹参方剂（HDD）是一种在治疗慢性肾脏病方面具有良好疗效的中药对，但作用机制尚需阐明。
通过网络药理学（NP）分析和实验验证，揭示 HDD 拮抗肾纤维化的潜在机制。
采用超高效液相色谱与 Q-Exactive 质谱联用（UHPLC-QE-MS）结合 HERB 数据库分析 HDD 水提物的化学成分。采用 NP 鉴定 HDD 成分与肾纤维化的核心共有靶标。随后，雄性 C57BL/6 小鼠分为假手术组、单侧输尿管梗阻（UUO）组和 UUO+HDD 组。采用肾功能、组织病理学、Western blot 和免疫组化分析评估 HDD 对 UUO 小鼠的保护作用。在 UUO 小鼠和转化生长因子-β1（TGF-β1）诱导的 HK-2 细胞中验证 HDD 对信号通路的影响。
通过 UHPLC-QE-MS 分析和 HERB 数据库结合，筛选出 HDD 提取物中的 25 种成分。25 种成分与肾纤维化的共有 270 个交集靶标。基于其在蛋白质-蛋白质相互作用分析中的得分和成分-通路-靶标三网络中的程度值，确定了 25 种成分与肾纤维化的 6 个核心共有靶标，即磷酸肌醇 3-激酶（PI3K）、信号转导和转录激活因子 3（Stat3）、非受体酪氨酸激酶Src（Src）、表皮生长因子受体（EGFR）、基质金属蛋白酶 9（MMP9）和 MMP2。HDD 改善了 UUO 小鼠的肾小管损伤和胶原沉积，并下调了纤维化相关蛋白的表达。此外，HDD 被证明可降低 UUO 小鼠肾脏和 TGF-β1 诱导的 HK-2 细胞中 PI3K、Stat3、Src、EGFR 和 MMP2 的表达，同时增强 MMP9 的表达。
HDD 可减轻肾纤维化，这可能与调节上皮间质转化和细胞外基质产生/降解信号通路中关键蛋白的表达有关。
