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Article(id=1211269040870396524, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269034906088369, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.03.13, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1599062400000, receivedDateStr=2020-09-03, revisedDate=1608912000000, revisedDateStr=2020-12-26, acceptedDate=null, acceptedDateStr=null, onlineDate=1766718643634, onlineDateStr=2025-12-26, pubDate=1616860800000, pubDateStr=2021-03-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766718643634, onlineIssueDateStr=2025-12-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766718643634, creator=13701087609, updateTime=1766718643634, updator=13701087609, issue=Issue{id=1211269034906088369, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='3', pageStart='213', pageEnd='318', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766718642212, creator=13701087609, updateTime=1766718779849, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1211269612247838856, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269034906088369, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1211269612247838857, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269034906088369, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=294, endPage=299, ext={EN=ArticleExt(id=1211269041717645960, articleId=1211269040870396524, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress of the curative effects of main active components of Astragalus membranaceus in treatment of diabetic nephropathy, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Diabetic nephropathy (DN) is a common complication of diabetes, and is one of the main causes of end stage renal disease (ESRD). At present, the practical therapeutic method for DN is still lacked due to unclear pathogenesis. However, as a traditional Chinese medicine, astragalus, especially Astragalus membranaceus, is commonly used in the treatment of DN. The main active ingredients of Astragalus membranaceus include astragaloside Ⅳ (AS-Ⅳ) and astragalus polysaccharide (APS), which can effectively reduce proteinuria and protect renal function. The mechanism of AS-Ⅳ and APS in treatment of DN was reviewed in present article including regulation of endoplasmic reticulum stress (ERS), anti-inflammatory, reducing cell apoptosis, inhibiting fibrosis, and regulating metabolism of sugar and lipid, in order to provide reference for the research and clinical application.

, correspAuthors=Xiang-Mei Chen, authorNote=null, correspAuthorsNote=
*E-mail:
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糖尿病肾病(DN)是糖尿病的常见并发症，是最终导致终末期肾病(ESRD)的主要原因之一。目前，由于DN的发病机制尚未明确，所以缺乏有效的治疗措施。黄芪作为我国的传统中药材，常用于DN的治疗。黄芪中含有黄芪甲甙(AS-Ⅳ)及黄芪多糖(APS)两种主要活性成分，可有效减轻蛋白尿，保护肾脏功能。该文从调节内质网应激(ERS)、抗炎、减少细胞凋亡、抑制纤维化、调节糖脂代谢等方面对AS-Ⅳ及APS治疗DN的机制进行综述，为其进一步应用于DN的临床治疗提供依据。

, correspAuthors=陈香美, authorNote=null, correspAuthorsNote=
陈香美，E-mail：
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倪慧明，硕士研究生，主要从事糖尿病肾病方面的研究。E-mail：

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倪慧明，硕士研究生，主要从事糖尿病肾病方面的研究。E-mail：

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黄芪主要活性成分对糖尿病肾病的疗效机制研究进展
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倪慧明 1, 2 , 董哲毅 2 , 陈香美 1, 2, *
解放军医学杂志 | 综述 2021,46(3): 294-299
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解放军医学杂志 | 综述 2021, 46(3): 294-299
黄芪主要活性成分对糖尿病肾病的疗效机制研究进展
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倪慧明1, 2 , 董哲毅2, 陈香美1, 2, *
作者信息
  • 1广东药科大学中药学院，广州 510006
  • 2解放军总医院肾脏病科/解放军肾脏病研究所/肾脏疾病国家重点实验室/国家慢性肾病临床医学研究中心/肾脏疾病研究北京市重点实验室，北京 100853

    • 倪慧明，硕士研究生，主要从事糖尿病肾病方面的研究。E-mail：

通讯作者:

陈香美，E-mail：
Research progress of the curative effects of main active components of Astragalus membranaceus in treatment of diabetic nephropathy
Hui-Ming Ni1, 2 , Zhe-Yi Dong2, Xiang-Mei Chen1, 2, *
Affiliations
  • 1School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
  • 2Department of Nephrology, Chinese PLA General Hospital/Chinese PLA Institute of Nephrology/State Key Laboratory of Kidney Diseases/National Clinical Medicine Research Center for Chronic Kidney Diseases/ Beijing Key Laboratory of Kidney Diseases, Beijing 100853
出版时间: 2021-03-28 doi: 10.11855/j.issn.0577-7402.2021.03.13
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摘要
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糖尿病肾病(DN)是糖尿病的常见并发症，是最终导致终末期肾病(ESRD)的主要原因之一。目前，由于DN的发病机制尚未明确，所以缺乏有效的治疗措施。黄芪作为我国的传统中药材，常用于DN的治疗。黄芪中含有黄芪甲甙(AS-Ⅳ)及黄芪多糖(APS)两种主要活性成分，可有效减轻蛋白尿，保护肾脏功能。该文从调节内质网应激(ERS)、抗炎、减少细胞凋亡、抑制纤维化、调节糖脂代谢等方面对AS-Ⅳ及APS治疗DN的机制进行综述，为其进一步应用于DN的临床治疗提供依据。

糖尿病肾病  /  黄芪甲甙  /  黄芪多糖

Diabetic nephropathy (DN) is a common complication of diabetes, and is one of the main causes of end stage renal disease (ESRD). At present, the practical therapeutic method for DN is still lacked due to unclear pathogenesis. However, as a traditional Chinese medicine, astragalus, especially Astragalus membranaceus, is commonly used in the treatment of DN. The main active ingredients of Astragalus membranaceus include astragaloside Ⅳ (AS-Ⅳ) and astragalus polysaccharide (APS), which can effectively reduce proteinuria and protect renal function. The mechanism of AS-Ⅳ and APS in treatment of DN was reviewed in present article including regulation of endoplasmic reticulum stress (ERS), anti-inflammatory, reducing cell apoptosis, inhibiting fibrosis, and regulating metabolism of sugar and lipid, in order to provide reference for the research and clinical application.

diabetic nephropathy  /  astragaloside Ⅳ  /  astragalus polysaccharide
倪慧明, 董哲毅, 陈香美. 黄芪主要活性成分对糖尿病肾病的疗效机制研究进展. 解放军医学杂志, 2021 , 46 (3) : 294 -299 . DOI: 10.11855/j.issn.0577-7402.2021.03.13
Hui-Ming Ni, Zhe-Yi Dong, Xiang-Mei Chen. Research progress of the curative effects of main active components of Astragalus membranaceus in treatment of diabetic nephropathy[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (3) : 294 -299 . DOI: 10.11855/j.issn.0577-7402.2021.03.13
正文
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糖尿病肾病(diabetic nephropathy，DN)是典型的糖尿病微血管病变[1]，也是糖尿病最常见的并发症[2]。近年来，DN的发病率急剧增高，1980—2019年中国约有21.8%的2型糖尿病患者罹患DN[3]。DN临床上常表现为尿白蛋白水平升高及肾小球滤过率降低，其机制为血流动力学的改变及肾小球滤过屏障受损[4-5]。DN患者的入球小动脉扩张及出球小动脉阻力增加，使肾小球呈高灌注、高滤过状态，从而导致肾小球系膜细胞增生、基底膜增厚，肾小球硬化伴结节性系膜病变等组织病理学改变[6]。目前，血管紧张素转换酶抑制剂及血管紧张素受体阻滞剂的应用是延缓DN进程的重要手段，但仍然有较多患者继续进展至终末期肾病(end stage renal disease，ESRD)[7]。新近的研究表明，钠-葡萄糖共转运蛋白2抑制剂可有效降低血糖，控制蛋白尿的发生，降低肾衰竭及心血管事件的发生率[8]，对DN有良好的治疗作用，但有小部分患者在使用此药物时会出现生殖器真菌感染、糖尿病酮症酸中毒等不良反应[9]。因此，为了有效控制DN的发展，阻止DN进程，须探索更多高效、安全的治疗药物。
在我国，以黄芪为代表的中草药已广泛应用于DN的临床治疗。黄芪是豆科多年生草本植物——蒙古黄芪Astragalus membranaceus (Fisch.) Bge.var. mongholicus (Bge.) Hsiao或膜荚黄芪Astragalus membranaceus (Fisch.) Bge.的干燥根，具有补气升阳，利尿消肿等功效[10]。黄芪所含化学成分复杂，主要包括黄酮类、皂苷类、多糖类及氨基酸类物质[11]。其中黄芪甲甙(astragaloside Ⅳ，AS-Ⅳ)及黄芪多糖(astragalus polysaccharide，APS)是其主要活性成分[12-13]。本文主要对AS-Ⅳ及APS治疗DN的机制进行综述，旨在为其进一步的药理研究及临床应用提供理论依据。
1 黄芪主要活性成分的药理作用
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AS-Ⅳ及APS均具有抗炎、抗氧化、免疫调节、抗肿瘤等药理作用[12-14]。AS-Ⅳ可抑制促炎细胞因子的产生，增加γ干扰素的基因表达，增强免疫应答，对扩张型心肌病、乙型肝炎病毒感染等疾病具有潜在的治疗作用；调节线粒体自噬，保护线粒体功能，发挥抗氧化活性[14]；调节过度免疫反应，增加细胞毒性T淋巴细胞，从而减少肿瘤细胞的侵袭及转移，控制肿瘤进展；还可治疗多发性硬化、类风湿关节炎等自身免疫性疾病[12]。许多研究表明，AS-Ⅳ对心[15]、肺[16]、肾脏[17]及神经系统[18]均有保护作用。APS可通过增强T细胞、B细胞等免疫细胞的功能，提高免疫调节活性[13]。有研究发现，APS对肾结石有预防和治疗作用[19]。此外，APS不仅能增强化疗药物的抗癌作用[14]，还能明显抑制并杀灭肿瘤细胞[20]。
2 黄芪主要活性成分对DN的疗效作用机制
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DN发病机制复杂，多种致病因素如内质网应激(endoplasmic reticulum stress，ERS)、炎症、细胞损伤及凋亡、肾组织纤维化、糖脂代谢异常等，均可导致糖尿病肾损害。AS-Ⅳ及APS对上述致病因素具有明显的抑制及改善作用。
2.1 调节内质网应激
内质网是蛋白质折叠的“工厂”，是分泌性蛋白及生物膜蛋白加工并转运至高尔基体的关键场所，也是细胞内Ca2+存储的重要部位。当发生某些病理生理应激时，会导致内质网腔内众多未折叠蛋白及错误折叠蛋白积聚，内质网内环境及Ca2+稳态失衡，从而引发过度的ERS[21]。内质网膜上存在3种蛋白传感器——蛋白激酶R样内质网激酶(protein kinase RNA-like ER kinase，PERK)、肌醇依赖酶1α(inositol-requiring enzyme 1α，IRE1α)及活化转录因子6(activating transcription factor 6，ATF6)，均为介导ERS的重要分子，能够调节内质网级联反应通路[22]。ERS参与了包括DN在内的多种肾脏疾病的病理生理过程，因此，通过药物治疗恢复内质网功能的平衡，是预防或阻止肾脏疾病进展的有效方法[23]。有研究发现，APS可通过抑制PERK磷酸化，降低ERS标志物CCAAT/增强子结合蛋白(CCAAT/enhancer binding protein，C/EBP)的同源蛋白(C/EBP homologous protein，CHOP)水平，从而恢复内质网功能稳态[24]。Guo等[25-26]采用自发性和诱发性两种糖尿病动物模型，即db/db小鼠和链脲佐菌素(streptozotocin，STZ)诱导的糖尿病小鼠进行研究，均发现小鼠肾脏组织中PERK、IRE-1α、ATF6及其下游靶点被激活，CHOP表达明显升高，磷酸化c-Jun氨基末端激酶(c-JunN-terminalkinase，JNK)和裂解的半胱氨酸天门冬氨酸蛋白水解酶(caspase)-12等ERS诱导细胞凋亡的因子表达增加，以上情况均可由AS-Ⅳ逆转。另有研究发现，AS-Ⅳ可减少DN大鼠肾组织中ERS标志物——葡萄糖调节蛋白78(glucose-regulated protein78，GRP78)的表达，抑制过度ERS的发生[27]。综上，黄芪的主要活性成分可通过抑制PERK、IRE-1α、ATF6所介导的ERS信号通路的活化，降低CHOP、GRP78等ERS相关蛋白的表达水平，从而减轻ERS及其诱导的细胞凋亡，发挥对DN的保护作用。
2.2 抗炎、减少细胞凋亡
2.2.1 抗炎
炎症是DN病程进展的中心环节。在DN动物模型及患者肾组织中均发现炎性细胞浸润，随着炎性细胞大量聚集，肾小球、肾小管出现严重损害。因此，抗炎是减缓DN进展的有效方式之一。在DN病理发展过程中，不同的代谢途径及细胞因子被激活，如Janus激酶/信号转导和转录激活因子(Janus tyrosine kinase/signal transducer and transcription activator，JAK/STAT)信号通路，核转录因子κB(the nuclear transcription factor kappa B，NF-κB)、核转录因子E2相关因子2(nuclear factor erythroid 2-related factor 2，Nrf2)等[28]。AS-Ⅳ可通过作用于以上通路或细胞因子，减轻炎症反应及细胞凋亡[29-31]。单核细胞趋化蛋白-1(monocyte chemoattractant protein 1，MCP-1)是影响DN患者体内巨噬细胞积聚的关键，而某些炎性因子诱导的MCP-1表达则成为肾脏炎症发生的启动因素。有观点认为，肿瘤坏死因子(tumor necrosis factor，TNF)-α是MCP-1最有效的诱导剂[28]。AS-Ⅳ可抑制db/db小鼠MCP-1及TNF-α的表达上调，减轻肾脏炎症，降低蛋白尿，有效改善肾小球肥大及系膜基质增厚[25]。
2.2.2 减少足细胞凋亡
足细胞是维持肾小球滤过膜屏障功能及结构的主要细胞，也称肾小球脏层上皮细胞。目前，保护足细胞已成为治疗肾小球损伤的有效方式之一[32]。微小RNA(microRNA，miRNA)及长链非编码RNA(long non-coding RNA，lncRNA)与足细胞的损伤及凋亡密切相关，二者均属于非编码RNA，可以RNA的形式参与蛋白编码基因的调控。TNF受体相关因子5(tumor-necrosis factor receptor-associated factor 5，TRAF5)是TRAF家族的成员之一，参与NF-κB等炎性因子的激活，TRAF5过表达可明显抑制细胞活性，诱导足细胞凋亡[33]。研究发现，AS-Ⅳ可使高糖诱导的小鼠足细胞miR-378表达增高，而miR-378可靶向负调控TRAF5，因此，AS-Ⅳ可通过miR-378/TRAF5信号通路抑制足细胞凋亡，miR-378及TRAF5可作为治疗DN的新靶点[34]。DN还受某些lncRNA的调节。研究发现，长链非编码RNA-牛磺酸上调基因1(lncRNA-TUG1)与TRAF5表达呈负相关，而AS-Ⅳ可调节二者的平衡，通过升高lncRNA-TUG水平，降低TRAF5的过表达，从而减轻高糖诱导的足细胞凋亡，对DN起靶向治疗作用[35]。
2.2.3 减少内皮细胞凋亡
内皮功能障碍是DN的病理特征之一[36]。内皮型一氧化氮合酶(endothelial NO synthase，eNOS)在肾脏疾病中不仅发挥调节血管生成的作用，还能修复内皮细胞损伤，激活内皮细胞一氧化氮(nitric oxide，NO)的释放。糖尿病患者体内eNOS活性受到抑制，NO的生成量及生物利用度大大降低，导致内皮功能障碍，成为DN的起始环节[37]。eNOS的活性还可通过其磷酸化来调节。AS-Ⅳ可加速DN大鼠体内血清及肾组织中的NO合成，促进eNOS磷酸化，明显增强其活性，减轻内皮细胞损伤，同时在高糖环境下，AS-Ⅳ还可降低人肾小球内皮细胞的通透性，减少细胞凋亡[38]。
2.2.4 减少肾小管上皮细胞凋亡
DN的病理因素还包括肾小管上皮细胞损伤，当其损伤加重时，可加速DN向ESRD的进展[39]。Ju等[27]建立高脂饮食及小剂量STZ诱导的DN大鼠模型，模型组出现典型的肾小管上皮细胞损伤表现，包括肿胀、肥大、脱落，肾小管空泡样变、基底膜增厚，间质胶原沉积等特征性病理改变，AS-Ⅳ治疗后上述组织病理学改变明显好转，凋亡相关蛋白Bax/Bcl-2的比值下调，裂解的caspase-3表达水平降低，细胞凋亡减少。Wang等[31]采用TUNEL染色法检测高糖诱导的HK-2细胞凋亡情况，模型组中阳性细胞数量明显多于对照组，而经AS-Ⅳ处理后HK-2凋亡明显减少。Nrf2是外源性毒性物质及氧化应激的靶点，具有关键的防御效应。抗氧化反应元件(antioxidant response element，ARE)可启动解毒及抗氧化应激的基因转录，保护细胞生物系统免受外源性毒物及氧化剂的损害[40]。AS-Ⅳ可增强Nrf2及其下游基因——血红素加氧酶-1(HO-1)、Kelch样环氧氯丙烷相关蛋白1(Keap1)、醌氧化还原酶1(NQO1)mRNA的表达，调节Nrf2/ARE信号通路，从而对高糖诱导的HK-2细胞凋亡及氧化应激损伤发挥保护作用[31]。APS也具有同样显著的效应。在高糖条件下，APS可通过下调JAK/STAT信号通路，抑制HK-2细胞凋亡及转分化的发生，并能减少细胞内活性氧簇(Reactive oxygen species，ROS)的生成和氧化损伤[29]。APS对HK-2细胞的保护作用还与其抑制Wnt信号通路相关[41]。由此可见，黄芪主要活性成分能够抑制Bax、caspase-3等细胞凋亡蛋白的表达，增强Nrf2及其靶基因HO-1、Keap1、NQO1的mRNA表达水平，调节Nrf2/ARE通路，减轻氧化应激导致的细胞损伤，并可抑制JAK/STAT及Wnt信号通路，减少肾小管上皮细胞凋亡，最终延缓DN的病理进程。
2.3 抑制纤维化进程
在DN进展过程中，细胞外基质(extracellular matrix，ECM)过度沉积可导致肾纤维化的发生。转化生长因子-β1(transforming growth factor-β1，TGF-β1)是肾脏炎症及纤维化发展的重要因子，与上皮-间质转化(epithelial-mesenchymal transition，EMT)密切相关，TGF-β1过表达可加剧ECM的累积。Wang等[30]发现，在高糖诱导的小鼠永生化足细胞中，AS-Ⅳ可抑制TGF-β1的表达，并可激活沉默信息调节因子1(silent information regulator 1，SIRT1)-NF-κB通路，抑制高糖诱导的足细胞EMT；此外，AS-Ⅳ可减少KK-Ay小鼠的微量白蛋白尿，并减轻ECM的过度沉积及肾脏纤维化。TGF-β1可通过调控下游的信号分子发挥其生物学效应。Smad3及Smad7均为TGF-β1的下游分子。在高糖条件下，Smad3表达增多可引发肾脏纤维化及炎症，进而导致肾功能障碍[42]。同时，Smad7可负调控Smad3的活化。Mao等[43]研究发现，AS-Ⅳ可降低miR-192和TGF-β1、Smad3、肌动蛋白α、Ⅰ型胶原蛋白等纤维化相关蛋白的表达，增加Smad7的表达，并呈剂量依赖性地减轻高糖诱导的大鼠系膜细胞增殖，其机制可能是通过TGF-β1/Smad/miR-192通路抑制肾纤维化的产生及系膜细胞的过度增殖。
基质金属蛋白酶(matrix metalloproteinase，MMP)为一类含锌的肽链内切酶，可降解ECM，是观察DN预后的重要因子。组织金属蛋白酶抑制因子(tissue inhibitor of matrix metalloproteinases，TIMP)为MMP的抑制剂，这两种蛋白对维持ECM合成及降解的平衡具有积极的作用[40]。有研究发现，APS可抑制TGF-β1/Smad信号通路，调控其下游信号分子，升高MMP-2、MMP-9的表达，并降低TIMP-1、TIMP-2的表达，最终可减轻肾脏纤维化损伤[44]。
2.4 调节糖、脂代谢
众所周知，糖类及脂肪代谢异常是糖尿病的典型特征。在2型糖尿病的进程中，代谢器官及组织中胰岛素敏感性逐渐丧失，出现胰岛素抵抗，最终发生胰岛β细胞功能衰竭，导致高血糖及其他并发症的发生。改善胰岛素敏感性是治疗2型糖尿病及DN等代谢性疾病的有效方式。脂肪组织是胰岛素刺激葡萄糖摄取的主要靶点，胰岛素抵抗则会影响葡萄糖的摄取。过氧化物酶体增殖物激活受体γ(peroxisome proliferator activated receptor γ，PPARγ)及C/EBPα是脂肪细胞形成过程中的两个关键转录因子，可诱导前体脂肪细胞向脂肪细胞分化，参与葡萄糖和脂质代谢。Zhang等[45]采用小鼠3T3-L1前体脂肪细胞进行研究，发现APS可促进细胞增殖，使细胞内PPARγ和C/EBPα的表达升高，此外，负责摄取葡萄糖的主要转运蛋白——葡萄糖转运蛋白4(glucose transporter 4，Glut4)的mRNA及蛋白表达水平升高，且AMP依赖的蛋白激酶(AMPK)含量也明显增加。AMPK参与了机体的能量代谢过程，是调控能量代谢及胰岛素敏感性的中间环节，其活性与胰岛素敏感性呈正相关。以上结果均表明，APS可增加脂肪细胞对葡萄糖的摄取，并激活AMPK，从而提高胰岛素敏感性。
AS-Ⅳ是一种新型的PPARγ激动剂[46]，可增强db/db小鼠PPARγ的表达，从而调节小鼠体内的葡萄糖稳态及脂质代谢[25]。以PPARγ为靶点进行靶向治疗是维持血糖水平和脂质稳态的有效方式。肾脏内脂质沉积及过量游离脂肪酸(free fatty acids，FFAs)累积可导致肾小管上皮细胞损伤，而AS-Ⅳ可减少脂质在HK-2细胞内的沉积，减轻细胞损伤及凋亡[47]。体内脂质代谢异常可导致肾脏纤维化，而恢复脂肪酸代谢则可避免肾脏纤维化的发生[48]。Su等[49]发现，AS-Ⅳ可下调棕榈酸酯诱导的人肾小球系膜细胞(human glomerular mesangial cells，HMCs)中CD36的表达，减少FFAs的吸收，从而抑制HMCs纤维化及氧化应激的发生。CD36是FFAs摄取的主要转运蛋白，在调控糖尿病等代谢性疾病中具有重要意义。
3 总结与展望
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在DN等代谢性疾病的治疗过程中，寻找有效的靶向治疗方案十分关键。国际上对中医药治疗越来越重视，且对中药的药理研究也日渐深入。黄芪是中医组方应用中最经典、最常用的中药之一，其主要活性成分AS-Ⅳ及APS在治疗DN方面具有积极的作用。首先，可抑制PERK、IRE-1α、ATF6等介导ERS发生的主要分子的活化，调节内质网级联反应通路，恢复内质网功能稳态，预防DN进展；其次，作用于肾小管上皮细胞，下调JAK/STAT信号通路及Wnt信号通路，上调Nrf2/ARE信号通路，从而抑制细胞凋亡，抑制高糖诱导的足细胞NF-κB、MCP-1、TNF-α等炎性因子的表达，减轻肾脏炎症反应；再次，作用于系膜细胞，可抑制TGF-β1/Smad信号通路，减轻系膜细胞的异常增殖，调控MMP系列分子，平衡ECM的合成与降解，减轻肾脏的纤维化程度；最后，增加PPARγ及C/EBPα的表达，提高胰岛素敏感性，增强脂肪细胞摄取葡萄糖的能力，减轻糖脂代谢紊乱。
有学者基于系统药理学的方法，从分子水平到病理水平深入探讨了AS-Ⅳ治疗DN的作用机制，发现AS-Ⅳ可通过多靶点多通路协同治疗DN，为后续探索中药有效成分提供了全新的方法及思路[50]。目前，黄芪及其活性成分APS、AS-Ⅳ均已研制出注射剂型，但未广泛应用于临床，不良反应也未见明确报道。因此，未来须更深入而全面地挖掘黄芪活性成分的药理作用，以期为DN的临床治疗提供更为可靠的理论依据。
基金
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  • 国家自然科学基金(81700629)
  • 国家重点研发计划(2016YFC1305503)
  • 国家重点研发计划(2018YFC1704203)
  • 北京市科技计划(D171100002817002)
文献
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doi: 10.11855/j.issn.0577-7402.2021.03.13
  • 接收时间：2020-09-03
  • 首发时间：2025-12-26
  • 出版时间：2021-03-28
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  • 收稿日期：2020-09-03
  • 修回日期：2020-12-26
基金
National Natural Science Foundation of China(81700629)
国家自然科学基金(81700629)
National Key Research and Development Program(2016YFC1305503)
国家重点研发计划(2016YFC1305503)
National Key Research and Development Program(2018YFC1704203)
国家重点研发计划(2018YFC1704203)
Science and Technology Project of Beijing(D171100002817002)
北京市科技计划(D171100002817002)
作者信息
    1广东药科大学中药学院，广州 510006
    2解放军总医院肾脏病科/解放军肾脏病研究所/肾脏疾病国家重点实验室/国家慢性肾病临床医学研究中心/肾脏疾病研究北京市重点实验室，北京 100853

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陈香美，E-mail：
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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