Cornus officinalis var. koreana Kitam extracts alleviate cadmium-induced renal fibrosis by targeting matrix metallopeptidase 9
Cornus officinalis var. koreana Kitam extracts alleviate cadmium-induced renal fibrosis by targeting matrix metallopeptidase 9
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DOI：
10.1016/j.jep.2024.117824
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发表时间：
2024-02-03
影响因子：
5.4
通讯作者：
Lou，Qiang
中科院分区：
文献类型：
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作者：
Wang，Zhonghang;Yin，Guanyi;Lou，Qiang
山茱萸（Cornus officinalis var.koreanaKitam）是一种常用的中草药，对肾脏和肝脏疾病具有良好的临床疗效。近年来，多项研究报道山茱萸对肾纤维化有显著的影响.然而，其潜在的具体机制、生物活性成分和靶基因调控网络仍不清楚。研究目的：本研究探讨山茱萸提取物对镉诱导的肾纤维化的影响，采用药理子网络分析法筛选山茱萸的活性成分，探讨山茱萸提取物对靶基因基质金属肽酶9（MMP 9）的调节作用。6 N小鼠用单一或组合药剂如盐水、氯化镉、山茱萸、异银杏黄酮和FSL-1处理。Isoginkgetin是一种具有抗MMP 9活性的化合物。FSL-1可诱导MMP 9的表达。Masson染色、Western blot和免疫组织化学分析用于评估肾纤维化。此外，采用BUMPT（Boston university mouse proximal tubular）细胞建立创伤愈合模型，研究山茱萸对镉诱导的细胞迁移的影响。采用超高效液相色谱-质谱联用技术（UHPLC-MS）对山茱萸中的主要活性成分进行了鉴定。结果山茱萸水提物对氯化镉诱导的小鼠肾功能不全和肾纤维化有保护作用，体外实验证实山茱萸水提物抑制细胞迁移能力，尤其是在氯化镉条件下。子网络分析和化学成分谱分析技术揭示了山茱萸的活性成分。细胞热位移实验验证了三种活性成分大豆苷元、N-乙酰-L-酪氨酸和獐牙菜素与基质金属蛋白酶9的结合能力。明胶酶谱分析显示，三种活性成分均抑制了MMP 9的活性。进一步证实了MMP 9参与了山茱萸提取物减轻镉致大鼠肾纤维化的过程，山茱萸减轻镉致大鼠肾纤维化与降低MMP 9、I型胶原、α-SMA的表达有关结论山茱萸提取物可能通过抑制基质金属蛋白酶9，为进一步研究山茱萸抗肾纤维化的作用机制提供了新的思路。
Ethnopharmacological relevanceCornus officinalis var.koreanaKitam(Cornus officinalis) is a commonly used Chinese herbal medicine and has a good clinical efficacy in kidney and liver diseases. Recent years, a number of studies reported the significant effects ofCornus officinalison renal fibrosis. However, it is still unclear about the underlying specific mechanism, the bioactive ingredients, and the target gene regulatory network.Aim of the study: We investigated the impact ofCornus officinalisextract on cadmium-induced renal fibrosis, screened the bioactive ingredients ofCornus officinalisusing a pharmacological sub-network analysis, and explored the regulatory effects ofCornus officinalisextracts on target gene matrix metallopeptidase 9 (MMP9).MethodsMale C57BL/6N mice were treated with single or combinatorial agents such as saline, cadmium chloride,Cornus officinalis, Isoginkgetin and FSL-1. Isoginkgetin is a compound with anti-MMP9 activity. FSL-1 can induce MMP9 expression. Masson staining and Western blot and immunohistochemistry analyses were used for assessing renal fibrosis. In addition, wound healing model was established using BUMPT (Boston university mouse proximal tubular) cells to investigate howCornus officinalisaffected cadmium-induced cell migration. The mainCornus officinalisbioactive compounds were identified by UHPLC-MS (Ultra-high-performance liquid chromatography - mass spectrometry). The MMP9 target forCornus officinalisactive ingredients were confirmed through a pharmacological sub-network analysis.ResultsAqueous extracts ofCornus officinalisprotected from renal dysfunction and kidney fibrosis induced by cadmium chloride in mice.In vitroexperiments validated thatCornus officinalisextracts inhibited cell migration ability especially in cadmium chloride condition. The sub-network analysis and chemical components profiling technique revealed the active compounds ofCornus officinalis. Cellular thermal shift assay verified the binding abilities of three active components Daidzein, N-Acetyl-L-tyrosine or Swertisin with matrix metalloproteinase-9. Gelatin zymography assay revealed that the activity of MMP9 was inhibited by the three active components. We further confirmed that MMP9 was involved in the process ofCornus officinalisextracts reducing renal fibrosis.Cornus officinalisattenuated the cadmium-induced renal fibrosis was correlated with decreased expression of MMP9, collagen I, α-SMA (alpha-smooth muscle actin) and vimentin.ConclusionsThis study demonstrated thatCornus officinalisextracts could alleviate the cadmium chloride-induced renal fibrosis by targeting MMP9, and might provide new insights into the mechanism of treating renal fibrosis byCornus officinalis.