摘要
糖尿病肾病(diabetic kidney disease, DKD)是糖尿病严重的并发症之一,也是导致终末期肾病(end-stage renal disease, ESRD)发生的重要因素。DKD主要临床表现为白蛋白尿和肾小球滤过率下降,严重影响了患者的生活质量,并带来巨大的经济负担。中药(traditional Chinese medicine, TCM)在治疗糖尿病肾病中积累了丰富的经验。本文从中药成分、药对、中药复方3个方面对近年来中药治疗DKD的研究进展进行分析总结,以期为广大研究者实验研究提供新思路。
糖尿病肾病(diabetic kidney disease,DKD)是糖尿病常见的微血管并发症之一,糖尿病肾病发病隐匿,进展迅速,机制复杂。是由高血糖状态下导致的氧化应激反应、代谢异常以及肾脏血流量动力学改变。主要特征是肾小球系膜扩张、肾小管间质纤维化、肾小球基底膜增厚和肾小球高滤过伴微量白蛋白尿。持续性蛋白尿和肾小球滤过率降低逐渐导致终末期肾病。且糖尿病相关肾病见于约40%的2型糖尿病患
在中医理论体系中,DKD并无特定的病名称谓,而是根据患者临床表现归属于中医学中的消渴病范畴,“消渴”一词首见于《素问·奇病论篇》,“肥者,令人内热,甘者令人中满,故其气上溢,转为消渴。”文中指出消渴是饮食不节,脾胃失运化的结果。《金匮要略》设专篇讨论,最早提出了治疗方药。《圣济总录》载“消渴病久,肾气受伤,肾主水,肾气虚惫,气化失常,开阖不利,水液聚于体内而出现水肿。”文中指出消渴病是肾气不足,气化功能失常,津液聚集出现水肿的疾病。《素问·举痛论篇》载“百病皆生于气”,认为气是导致疾病的关键因素。后世医家对消渴病的病因病机认识也不尽相同。徐财彬
迄今为止,DKD的发病机制仍未阐明。但已知肾脏损伤与糖尿病进程是相互关联的(

图1 糖尿病肾病(DKD)的发病机制
AGEs:晚期糖基化终末产物(advanced glycosylation end products);MR:盐皮质激素受体(mineralocorticoid receptor);MCP-1:单核细胞趋化蛋白-1(monocyte chemotactic protein-1);ICAM-1:细胞间黏附分子1(intercellular cell adhesion molecule-1);PAI-1:纤溶酶原激活物抑制剂1(plasminogen activator inhibitor-1);CTGF:结缔组织生长因子(connective tissue growth factor)
肾素-血管紧张素-醛固酮系统(renin-angiotensin-aldosterone system, RAAS)的过度激活会导致进行性肾损
高葡萄糖环境下细胞内葡萄糖代谢产生AGEs增加,从而刺激细胞表面受体AGE受体(RAGEs),引起烟酰胺腺嘌呤二核苷磷酸(niacinamide adenine dinucleoside phosphate, NADPH)和活性氧(reactive oxygen species, ROS)水平的增加以及抗氧化酶活性的降低,中枢促炎途径的活性增加,NF-кB通路激活导致IL-6和TNF-α升高以及TGF-β的产生增加,引起肾组织中的氧化应激、慢性炎症和肾纤维化,最终导致肾功能丧失。AGE与RAGE结合激活不同细胞内信号通路,包括NF-кB、丝裂原活化蛋白激酶(mitogen activated protein kinase, MAPK)、PI3K/Akt/mTOR
研究表明,DKD患者与健康人群的肠内菌存在明显差异。且在高葡萄糖环境下,会刺激AGEs的产生,从而与肠道微生物群发生相互作用,导致局部炎症和炎症因子的释放。此外,DKD过程中肠道菌群改变,肠道通透性增加,从而促进了进入体循环的细菌及其代谢产物的增加,进而引发慢性炎症并诱导胰岛素抵
DKD发生与遗传因素密切相关,糖尿病及全基因组关研究揭示了DKD易感性。肾脏是一个复杂而又庞大的系统,其组织发生发展过程受到众多致病因子影响,其中包括多种基因簇及其他蛋白质组异常改变。长期以来,人们普遍认为编码肾小球基底膜(glomerular basement membrane, GBM)主要结构成分的COL4A3基因错义突变会导致Alport综合
深入探究DKD的发病机制为新的干预策略提供了科学依据,除了血管紧张素转换酶抑制剂(angiotensin converting enzyme inhibitor, ACE)或血管紧张素受体阻滞剂(angiotensin receptor blocker, ARB)等药物外,SGLT2抑制剂和非奈利酮(finerenone)新的治疗策略也相继被研发出来,但是这些治疗策略仍然存在残余风险与并发
中药活性成分为其发挥药效提供了物质基础,伴随着药物化学及药理研究的迅速发展,中药活性成分黄酮类、生物碱类、多糖类、皂苷类和醌类等已经被研究出具有抗炎、抗氧化、抗凋亡、调节代谢等作用,如淫羊藿苷、当归多糖、虎杖苷可通过抑制TLR4/NF-κB信号通路从而减轻肾组织中的炎症反应,延缓DKD的进展;以及水飞蓟素、川芎嗪等可激活Akt信号通路来改善DKD(

图2 中药活性成分改善DKD的作用机制
类型 | 中药活性 成分 | 动物/细胞模型 | 作用机制及相关信号通路 | 文献 |
---|---|---|---|---|
黄酮类 | 丹参酮ⅡA | 雄性SD大鼠,高脂+STZ诱导 | 抗氧化、抗炎 |
[ |
雄性SD大鼠,STZ诱导 | 减弱PERK途径诱导的纤维化 |
[ | ||
金丝桃苷 |
C57BLKS/6 | 促进巨噬细胞从M1到M2表型的极化和CD4T细胞分化为Th2和Treg群体来改善鼠DKD |
[ | |
槲皮素 | C57BL/KSJ db/db小鼠和HG诱导的MPs | 抑制EGFR信号通路减少足细胞凋亡 |
[ | |
山奈酚 | C57BLKS/J db/db小鼠 | 增加p-AMPK和降低p-mTOR表达来显著调控AMPK/mTOR信号通路 |
[ | |
NRK-52E细胞和RPTEC细胞,HG诱导 | 抑制RhoA/Rho激酶介导的炎症信号传导 |
[ | ||
雄性Wistar大鼠,STZ诱导 | 激活Nrf2信号通路 |
[ | ||
淫羊藿苷 | 雄性ICR小鼠,STZ诱导 | 抑制TLR4/NF-κB信号通路 |
[ | |
雄性SD大鼠,STZ诱导和HG诱导MPs细胞 | 抑制Keap3-Nrf1/HO-2轴的NLRP3炎症小体激活 |
[ | ||
水飞蓟素 | C57BL/KsJ db/db小鼠 | 激活Akt信号通路 |
[ | |
生物碱 | 小檗碱 | 雄性SD大鼠,STZ诱导 | 抑制TLR4/NF-κB途径 |
[ |
雄性C57BL/6小鼠,高脂+HG+STZ诱导和HG诱导GMCs | 抑制PI3K/Akt/AS160/GLUT1 |
[ | ||
雄性SD大鼠,STZ诱导 | 激活Nrf2信号通路 |
[ | ||
川芎嗪 | 雄性Wistar大鼠,STZ+NCT诱导 | 激活Akt信号通路 |
[ | |
甜菜碱 | db/db小鼠 | 减轻内质网应激及相关的炎症反应 |
[ | |
青藤碱 | 雄性SD大鼠,高脂+STZ诱导 | 抑制氧化应激,减少肾细胞凋亡和纤维化,调节DKD大鼠JAK2/STAT3/SOCS1途径来保护肾细胞并减少肾组织损伤 |
[ | |
皂苷类 | 菝葜皂苷元 | 雄性SD大鼠,STZ诱导 | 抑制NLRP3炎症小体活化和AGEs-RAGE相互作用 |
[ |
雄性SD大鼠,STZ诱导和HG诱导的MPs细胞 | 靶向GSK3β信号通路和恢复足细胞自噬 |
[ | ||
雄性SD大鼠,STZ诱导和HG诱导的HMCs | 下调PAR-1抑制慢性炎症 |
[ | ||
桔梗皂苷D | 雄性SD大鼠,高脂+STZ诱导 | 抑制肾组织PI3K/Akt/mTOR信号通路传导 |
[ | |
酸枣仁皂苷A | 雄性SD大鼠,高脂+STZ诱导 | 调控肾组织CaMKK2/AMPK/p-mTOR和PINK1/Parkin信号通路转导 |
[ | |
三七叶苷 | SD大鼠,STZ诱导 | 降低肾组织中MCP-1、CTGF蛋白表达水平 |
[ | |
黄芪甲苷Ⅱ | 雄性SD大鼠,STZ诱导 | 促进线粒体Mfn2、Fis1、p62、LC3、PINK1和Parkin的表达 |
[ | |
黄精皂苷 | Wistar大鼠,STZ诱导 | 抑制肾脏Wnt/β-catenin信号通路的转导 |
[ | |
多糖类 | 枸杞多糖 | 雄性大白兔,静脉注射ALX诱导 | 抑制NF-κB表达水平 |
[ |
黄芪多糖 | 雄性SD大鼠,高脂+STZ诱导 | 抑制TGF-β1/Smads信号通路 |
[ | |
灵芝多糖 | 昆明小鼠,STZ诱导 | 抑制NF-κB/NLRP3信号通路 |
[ | |
雄性SD大鼠,STZ诱导 | 干预PI3k/Akt/mTOR信号通路 |
[ | ||
当归多糖 | SD大鼠,高脂+STZ诱导 | 抑制TLR4/NF-κB信号通路 |
[ | |
柴胡多糖 | 雄性C57BL/6小鼠,STZ诱导 | 肾脏和结肠中炎症反应的表达减少,肠道菌群结构调整 |
[ | |
黄秋葵多糖 | 雄性C57BL/6小鼠,高脂+STZ诱导 | 激活AMPK/Sirt1/PGC-1α信号通路 |
[ | |
山药多糖 | SD大鼠,高脂饮食、肾切除+STZ诱导 | 大鼠肠道微生态变化发挥治疗作用 |
[ | |
醌类 | 大黄酸 | SD大鼠,高脂+STZ诱导 | 干预PI3K/Akt/FoxO1通路 |
[ |
白藜芦醇 | C57BL/KSJ db/db小鼠 |
改善肠道屏障功能,改善肠 道通透性和炎症状态,调节肠道微生物失调 |
[ | |
雄性SD大鼠,STZ诱导 | 调节AMPKα/mTOR信号通路 |
[ | ||
虎杖苷 | SD大鼠,高脂+STZ诱导 | 调节TLR4/NF-κB信号通路 |
[ |
STZ:链脲佐菌素;PERK:蛋白激酶R(PKR)样ER激酶(protein kinase RNA (PKR)-like endoplasmic reticulum kinase);BMDM:骨髓来源巨噬细胞(bone marrow-derived macrophage);MPs:小鼠足细胞(mouse podocytes);EGFR:表皮生长因子受体(epidermal growth factor receptor);NRK-52E:大鼠肾近端肾小管上皮细胞(rat renal proximal tubular epithelial cell);RPTEC:人肾近端小管上皮细胞(primary human renal proximal tubule epithelial cells);NLRP3:NOD样受体热蛋白结构域相关蛋白3(NOD-like receptor thermal protein domain associated protein 3);GMCs:肾小球系膜细胞(glomerular mesangial cells);NCT:烟酰胺;GSK3β:糖原合成酶激酶3β(glycogen synthase kinase-3beta);HMCs:人类系膜细胞(human mesangial cells);PAR-1:蛋白酶激活受体1(protease-activated receptor 1);CaMKK2钙钙调蛋白依赖激酶2:(calcium/calmodulin-dependent kinase kinase 2);PINK1:PTEN诱导激酶1(PTEN-induced putative kinase 1);MCP-1:单核细胞趋化蛋白1(monocyte chemoattractant protein-1);ALX:四氧嘧啶;PGC-1α:过氧化物酶体增殖物激活受体γ辅激活因子1α(peroxisome proliferator-activated receptor-γ co-activator-1α)
黄酮类成分主要通过抗炎、抗氧化、抗纤维化、抗凋亡、调节自噬等来发挥作用;生物碱类、皂苷类和多糖类活性成分都可以通过抗炎、抗氧化、抗纤维化来发挥对DKD的防治作用,除此之外,皂苷类还可以通过AGEs-RAGE相互作用来调节代谢,并通过调控肾组织CaMKK2/AMPK/p-mTOR和PINK1/Parkin信号通路转导来调节自噬;多糖类活性成分能调节肠道菌群来发挥对DKD的防治作用;醌类活性成分主要通过抗炎、自噬、调节肠道菌群等来发挥作用,其主要通过调节NF-κB相关信号通路来发挥抗炎作用,以及干预PI3K/Akt/FoxO1、AMPKα/mTOR信号通路来调节自噬。
中药药对是历代医家在长期临证中总结出来的经验,遵循中药配伍“相须、相使、相畏、相杀、相恶、相反”的配伍原则,从而达到增效减毒的作用。药对组成简单,但具备中药配伍的基本特点,被誉为连接单味药和复方药之间的桥梁。目前,由统计学归纳出能够治疗DKD的药对近30
黄芪甘、微温。归肺、脾经,具补气升阳,固表止汗,利水消肿,生津养血,行滞通痹,托毒排脓,敛疮生肌等作用,为“补气之长”。当归甘、辛,温。归肝、心、脾经。具有补血活血,调经止痛,润肠通便等功效,素有“补血之王”之称。两药配伍,可达益气生血,益气摄血,益气活血之
黄芪-山药药对源于《施今墨对药》:“治疗糖尿病,除滋阴清热外,健脾补气实为关键一环……黄芪甘温,入手足太阴气分,补气止消渴……”。山药归脾、肺、肾经,具有补脾养胃、生津益肺,补肾涩精的功能。二者合用,一则使脾气升,输布津液以止渴,二则使肾气固,封藏精微以缩尿。现代药理表明山药-黄芪抗DKD的作用机制可能与其调节体内代谢、抗氧
黄芪-山茱萸是近现代中医学界专家张锡纯临床上常用的药对,黄芪可补一身之气,山茱萸补益肝肾,收涩固脱,二药相配伍,调补脾肾之功增强。现代药理研究表明,黄芪可控制血糖和提高免疫耐受,对肾组织的抗氧化应激损伤有显着影响。山茱萸通过调节代谢紊乱、改善氧化应激、减轻炎症反应和调节足细胞来改善DK
黄芪汤由黄芪、茯苓、麦门冬、瓜蒌根、生地黄、北五味子、炙甘草组成,研究表明黄芪汤能浓度依赖地减轻db/db小鼠的体重,改善葡萄糖耐量,降低血糖,改善肾功能,从而改善DK
六味地黄丸源于《小儿药证直诀》,该方由熟地黄、酒萸肉、牡丹皮、山药、茯苓及泽泻组成,具有滋阴补肾的功效。现代研究表明,其具有抗炎、降血糖、改善肾脏功
黄连解毒汤出自《肘后备急方》,主要由黄连、黄芩、黄柏、栀子四味药组成,有清热解毒的功效。据报道,黄连解毒汤具有良好的DKD保护作用,能改善db/db小鼠糖脂代谢紊乱和肾损伤保护作用,可能的机制为抑制AGEs/RAGE通路、调控TGF-β1/p38MAPK信号通路、下调胱天蛋白酶3(caspase-3)的表达、抑制氧化应激、抑制细胞凋亡相
该制剂主要由黄芪、金樱子、蝉蜕、益母草、玉米须等中药组成,用于治疗慢性肾炎和慢性肾功能。黄乔木
DKD发展迅速,病机复杂,涉及到多种细胞因子及信号通路的变化,中药在治疗DKD的机制上表现出多成分,多途径,多靶点等特点,充分发挥了整体治疗的优势,其涉及的机制主要有抑制氧化应激、抗炎、抑制细胞凋亡、降血糖、改善肾脏功能等。本文所涉及的中药中,小檗碱对于防治DKD的报道较多,小檗碱对血糖、血脂和高血压方面的降低作用也得到了广泛研
中药成分复杂,其对DKD疗效及作用机制仍然面临着如下挑战:(1)文中涉及中药单体化合物、药对、复方对DKD的作用机制研究仍处于初步阶段,虽然有证据表明中药治疗DKD涉及抗炎、抗氧化、抗纤维化、调节代谢、调节肠道菌群等诸多方面,但是仍需要通过更多的体内外实验进行验证。未来将从DNA甲基化、组蛋白修饰等表观遗传改变及其与经典信号通路之间的关联出发,更加深入地揭示中药防治DKD的分子机制。(2)中医药在临床上已被广泛用于DKD的治疗,但由于中药成分复杂且物质基础尚不明确,临床佐证数据较少,仍需开展包含多中心、大样本、随机分组在内的具有严格设计规范的临床试验,同时结合多组学技术,以“整体”视角揭示中药对DKD作用机制。
以整体观与辨证论治为基础的中医药治疗策略可以根据DKD病理阶段的不同对DKD进行精准用药与个人化治疗。除此之外,伴随着“健康2030”作为国家战略的提出,人们对疾病的预防越来越关注。中医主张“治未病”的理念,其中包括未病先防、已病防变和已变防渐等诸多方面可制定个体化的辨证施治的方案,以达到平衡阴阳,标本兼治的目的。尤其是DKD的早期中医药干预是降低肾功能持续恶化的关键。基于DKD的病因病机防控,在未来将是中药防治DKD的重要应用。综上所述,中药在DKD的防治中有较广阔的应用前景。
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