基于YAP/TLRs通路探讨人参皂苷Rg_(2)对糖尿病视网膜病及血管增生的作用机制  

Mechanism of action of ginsenoside Rg_(2) on diabetic retinopathy and angiogenesis based on YAP/TLRs pathway

作　　者：刘卓容 宋勇丽 宁尚秋[2] 袁悦莹 张雨婷[1] 郝改梅 韩静[1] LIU Zhuo-rong;SONG Yong-li;NING Shang-qiu;YUAN Yue-ying;ZHANG Yu-ting;HAO Gai-mei;HAN Jing(Beijing University of Chinese Medicine,Beijing 102488,China;Beijing Anzhen Hospital,Capital Medical University,Beijing 100020,China;Institute of Basic Theory for Chinese Medicine,China Academy of Chinese Medical Sciences,Beijing 100700,China)

机构地区：[1]北京中医药大学,北京102488 [2]首都医科大学附属北京安贞医院,北京100020 [3]中国中医科学院中医基础理论研究所,北京100700

出　　处：《中国中药杂志》2025年第6期1659-1669,共11页China Journal of Chinese Materia Medica

基　　金：国家自然科学基金项目(82074238,81873165)。

摘　　要：人参皂苷Rg_(2)(ginsenoside Rg_(2),GRg2)是三七中一种三萜类化合物,该研究旨在探索GRg2对糖尿病视网膜病及血管增生的作用及机制。该研究采用葡萄糖或血管内皮生长因子(vascular endothelial growth factor,VEGF)诱导的内皮细胞模型、鸡胚绒毛膜(chorioallantoic membrane,CAM)模型、氧诱导的视网膜病变(oxygen-induced retinopathy,OIR)小鼠模型和db/db小鼠模型,以评价GRg2对糖尿病视网膜病及血管增生的治疗作用。采用Transwell实验和内皮管道形成实验检测细胞迁移和管道形成,应用血管面积检测血管增生,采取视网膜厚度、视网膜电图等检测GRg2对db/db小鼠视网膜结构和功能的影响,通过分析Yes相关蛋白(Yes-associatedprotein,YAP)及Toll样受体(Toll-like receptors,TLRs)通路的激活情况,探究GRg2的作用机制。结果显示,在体外GRg2可以显著降低细胞迁移数且减少管道形成长度;在CAM模型中GRg2呈剂量依赖性降低血管面积比例;在OIR模型中GRg2显著降低无血管面积与新生血管面积,改善视网膜结构紊乱;在db/db小鼠模型中GRg2增加视网膜总厚度,增加视网膜电图a波、b波和振荡电位(OPs)波振幅,改善视网膜结构紊乱;转录组研究结果显示,YAP敲减后TLRs信号通路显著下调,PCR结果与转录组测序结果保持一致;同时GRg2可在高糖诱导的内皮细胞中下调Toll样受体4(TLR4)、肿瘤坏死因子受体相关因子6(TNF receptor-associated factor 6,TRAF6)和核因子-κB(nuclear factor-kappaB,NF-κB)蛋白表达。综上所述,GRg2抑制细胞迁移和管道形成,并且显著减少CAM和OIR模型中的血管增生,改善db/db小鼠视网膜结构及功能,且其药理机制可能与下调YAP表达有关。Ginsenoside Rg_(2)(GRg2)is a triterpenoid compound found in Panax notoginseng.This study explored its effects and mechanisms on diabetic retinopathy and angiogenesis.The study employed endothelial cell models induced by glucose or vascular endothelial growth factor(VEGF),the chorioallantoic membrane(CAM)model,the oxygen-induced retinopathy(OIR)mouse model,and the db/db mouse model to evaluate the therapeutic effects of GRg2 on diabetic retinopathy and angiogenesis.Transwell assays and endothelial tube formation experiments were conducted to assess cell migration and tube formation,while vascular area measurements were applied to detect angiogenesis.The impact of GRg2 on the retinal structure and function of db/db mice was evaluated through retinal thickness and electroretinogram(ERG)analyses.The study investigated the mechanisms of GRg2 by analyzing the activation of Yes-associated protein(YAP)and Toll-like receptors(TLRs)pathways.The results indicated that GRg2 significantly reduced cell migration numbers and tube formation lengths in vitro.In the CAM model,GRg2 exhibited a dose-dependent decrease in the vascular area ratio.In the OIR model,GRg2 notably decreased the avascular and neovascular areas,ameliorating retinal structural disarray.In the db/db mouse model,GRg2 increased the total retinal thickness and enhanced the amplitudes of the a-wave,b-wave,and oscillatory potentials(OPs)in the ERG,improving retinal structural disarray.Transcriptomic analysis revealed that the TLR signaling pathway was significantly down-regulated following YAP knockdown,with PCR results consistent with the transcriptome sequencing findings.Concurrently,GRg2 downregulated the expression of Toll-like receptor 4(TLR4),TNF receptor-associated factor 6(TRAF6),and nuclear factor-kappaB(NF-κB)proteins in high-glucose-induced endothelial cells.Collectively,GRg2 inhibits cell migration and tube formation and significantly reduces angiogenesis in CAM and OIR models,improving retinal structure and function in db/db mice,with its pharmacologi

关 键 词：人参皂苷Rg_(2) 糖尿病视网膜病变 血管增生 Yes相关蛋白 TOLL样受体 

分 类 号：R285.5[医药卫生—中药学]