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Article(id=1202979640487928397, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1202979639087030850, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2952.2022.1124, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1640275200000, receivedDateStr=2021-12-24, revisedDate=null, revisedDateStr=null, acceptedDate=1661875200000, acceptedDateStr=2022-08-31, onlineDate=1764742296573, onlineDateStr=2025-12-03, pubDate=1690473600000, pubDateStr=2023-07-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764742296573, onlineIssueDateStr=2025-12-03, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764742296573, creator=13701087609, updateTime=1764742296573, updator=13701087609, issue=Issue{id=1202979639087030850, tenantId=1146029695717560320, journalId=1189873630562394117, year='2023', volume='48', issue='7', pageStart='749', pageEnd='870', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1764742296239, creator=13701087609, updateTime=1764742346610, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1202979850442203282, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1202979639087030850, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1202979850442203283, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1202979639087030850, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=856, endPage=862, ext={EN=ArticleExt(id=1202979640777335382, articleId=1202979640487928397, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress on genetic regulation mechanism of diabetes nephropathy, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Diabetic nephropathy (DN) is a chronic microvascular disease mainly secondary to diabetes. Its pathogenesis is affected by gene polymorphism, environmental factors, and so on. More and more studies have shown that epigenetic regulation mechanism without gene sequence changes plays an important role in occurrence and development of DN. The epigenetic regulation mechanism changes dynamically with the change of the surrounding environment. Transient environmental change, such as short-term high glucose, can lead to epigenetic regulation mechanism changes, affect histone exposed amino acid residue modification, DNA methylation level, etc., regulate the expression of related genes, and eventually promote the pathophysiological changes such as inflammation, hyperplasia and fibrosis. More interestingly, although the environmental stimulus disappeared, the epigenetic influence triggered by the initial stimulus still existed, with the phenomenon of "metabolic memory", suggesting that the change of epigenetic mechanism related to environmental stimulation may be the fundamental reason for the continuous progress of complications in diabetes patients, so effective intervention at the level of epigenetic mechanism also reveals new clinical therapeutic targets. The role of epigenetic regulation in the occurrence and development of DN has been reviewed in present paper, including epigenetic differences in DN, and the role of these differences-mediated signal pathway changes on kidney disease, and pay attention to the progress of epigenetic mechanism in treatment of the diseases, so as to provide a basis for clinical diagnosis and treatment of DN through epigenetic mechanism.

, correspAuthors=Kun-Ling Ma, authorNote=null, correspAuthorsNote=
* E-mail:
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糖尿病肾病(DN)是一种主要继发于糖尿病的慢性微血管疾病，其发病机制与基因多态性、环境因素等有关。越来越多的研究表明，不伴有基因序列变化的表观遗传调控机制在DN的发生发展中起重要作用。表观遗传调控机制随周围环境改变而呈动态变化，一过性的环境改变如短暂高糖等即可诱导表观遗传机制改变，影响组蛋白裸露氨基酸残基修饰、DNA甲基化水平等，并调控相关基因的表达，最终可促进炎症、增生、纤维化等病理生理改变。环境刺激消失后，其引起的表观影响仍持续存在，具有“代谢记忆”现象，提示环境刺激相关的表观遗传机制改变可能是糖尿病患者并发症持续进展的根本原因，而针对表观遗传机制层面的有效干预也揭示了新的临床治疗靶点。本文对表观遗传调控在DN发生发展中的作用进行综述，包括DN中存在的表观遗传差异性变化，以及这些变化介导的信号通路改变对肾脏疾病发生的作用，并关注基于表观遗传机制治疗疾病的进展情况，以期为临床从表观遗传机制层面诊断及治疗DN提供依据。

, correspAuthors=马坤岭, authorNote=null, correspAuthorsNote=
马坤岭，E-mail：
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黄玉林，硕士研究生，主要从事糖尿病肾病方面的研究

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黄玉林，硕士研究生，主要从事糖尿病肾病方面的研究

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黄玉林，硕士研究生，主要从事糖尿病肾病方面的研究

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糖尿病肾病遗传调控机制研究进展
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黄玉林 1 , 马坤岭 2, *
解放军医学杂志 | 综述 2023,48(7): 856-862
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解放军医学杂志 | 综述 2023, 48(7): 856-862
糖尿病肾病遗传调控机制研究进展
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黄玉林1, 马坤岭2, *
作者信息
  • 1东南大学附属中大医院肾内科，江苏南京 210009
  • 2浙江大学附属第二医院肾脏内科，浙江杭州 310000

    • 黄玉林，硕士研究生，主要从事糖尿病肾病方面的研究

通讯作者:

马坤岭，E-mail：
Research progress on genetic regulation mechanism of diabetes nephropathy
Yu-Lin Huang1, Kun-Ling Ma2, *
Affiliations
  • 1Institute of Nephrology, Zhongda Hospital Affiliated to S outheast University, Nanjing, Jiangsu 210009, China
  • 2Institute of Nephrology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310000, China
出版时间: 2023-07-28 doi: 10.11855/j.issn.0577-7402.2952.2022.1124
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摘要
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糖尿病肾病(DN)是一种主要继发于糖尿病的慢性微血管疾病，其发病机制与基因多态性、环境因素等有关。越来越多的研究表明，不伴有基因序列变化的表观遗传调控机制在DN的发生发展中起重要作用。表观遗传调控机制随周围环境改变而呈动态变化，一过性的环境改变如短暂高糖等即可诱导表观遗传机制改变，影响组蛋白裸露氨基酸残基修饰、DNA甲基化水平等，并调控相关基因的表达，最终可促进炎症、增生、纤维化等病理生理改变。环境刺激消失后，其引起的表观影响仍持续存在，具有“代谢记忆”现象，提示环境刺激相关的表观遗传机制改变可能是糖尿病患者并发症持续进展的根本原因，而针对表观遗传机制层面的有效干预也揭示了新的临床治疗靶点。本文对表观遗传调控在DN发生发展中的作用进行综述，包括DN中存在的表观遗传差异性变化，以及这些变化介导的信号通路改变对肾脏疾病发生的作用，并关注基于表观遗传机制治疗疾病的进展情况，以期为临床从表观遗传机制层面诊断及治疗DN提供依据。

糖尿病肾病  /  表观遗传学  /  代谢记忆

Diabetic nephropathy (DN) is a chronic microvascular disease mainly secondary to diabetes. Its pathogenesis is affected by gene polymorphism, environmental factors, and so on. More and more studies have shown that epigenetic regulation mechanism without gene sequence changes plays an important role in occurrence and development of DN. The epigenetic regulation mechanism changes dynamically with the change of the surrounding environment. Transient environmental change, such as short-term high glucose, can lead to epigenetic regulation mechanism changes, affect histone exposed amino acid residue modification, DNA methylation level, etc., regulate the expression of related genes, and eventually promote the pathophysiological changes such as inflammation, hyperplasia and fibrosis. More interestingly, although the environmental stimulus disappeared, the epigenetic influence triggered by the initial stimulus still existed, with the phenomenon of "metabolic memory", suggesting that the change of epigenetic mechanism related to environmental stimulation may be the fundamental reason for the continuous progress of complications in diabetes patients, so effective intervention at the level of epigenetic mechanism also reveals new clinical therapeutic targets. The role of epigenetic regulation in the occurrence and development of DN has been reviewed in present paper, including epigenetic differences in DN, and the role of these differences-mediated signal pathway changes on kidney disease, and pay attention to the progress of epigenetic mechanism in treatment of the diseases, so as to provide a basis for clinical diagnosis and treatment of DN through epigenetic mechanism.

diabetic nephropathy  /  epigenetic modifications  /  metabolic memory
黄玉林, 马坤岭. 糖尿病肾病遗传调控机制研究进展. 解放军医学杂志, 2023 , 48 (7) : 856 -862 . DOI: 10.11855/j.issn.0577-7402.2952.2022.1124
Yu-Lin Huang, Kun-Ling Ma. Research progress on genetic regulation mechanism of diabetes nephropathy[J]. Medical Journal of Chinese People’s Liberation Army, 2023 , 48 (7) : 856 -862 . DOI: 10.11855/j.issn.0577-7402.2952.2022.1124
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糖尿病肾病(diabetic nephropathy，DN)常继发于糖尿病，是一种慢性微血管疾病，已成为全球慢性肾脏病(chronic kidney disease，CKD)和终末期肾衰竭(end stage renal failure，ESRF)的主要原因[1]，且DN相关CKD或ESRF患者的病死率高于非DN患者[2]。作为糖尿病最常见的血管并发症之一，早期DN出现系膜肥大和肾小球高滤过伴微量白蛋白尿，临床表现不明显，但尿中微量白蛋白的增加常预示肾脏预后不良[3]，因此确诊糖尿病的患者，尤其是伴蛋白尿者，应在早期进行并发症筛查及定期随访[4]。患者若未行健康体检，或糖尿病确诊后未定期筛查，及至引起注意时往往已存在大量蛋白尿，且已发展至DN 4期，此时病情基本不可逆转。DN的肾脏病理损害几乎累及肾脏所有结构，病理表现为大量沉积的细胞外基质、足细胞病变、毛细血管网损伤、炎症细胞堆积等。DN的发病机制错综复杂，高血糖、高血压、高血脂等危险因素的影响和遗传易感性是其发生发展的重要因素。随着研究的深入，发现受代谢环境深刻影响的表观遗传调控机制在DN的发生发展中起重要作用。在糖尿病状态下，机体存在差异性的表观遗传机制改变，这些改变可能介导DN的持续进展。因此，本文对DN中存在的差异性表观遗传改变进行综述，包括表观遗传机制调控下表现出的“代谢记忆”现象，参与其中的DNA甲基化和组蛋白修饰改变等关键调控机制等，并总结此类表观遗传改变调控DN的信号通路及机制，以期为临床从表观遗传机制层面诊断及治疗DN提供依据。
1 遗传因素在DN发生中的作用
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DN主要继发于1型或2型糖尿病，全基因组研究显示人类基因组变异与糖尿病发生发展密切相关[5]。DN也存在多条通路上的基因变异，具有基因多态性[6]。世界公认的人类遗传病百科全书——在线人类孟德尔遗传数据库(Online Mendelian Inheritance in Man，OMIM，https://omim.org/)收录了大量糖尿病微血管并发症，包括DN相关的易感基因。
除了遗传易感性，传统的DN发病机制还包括肾小球血流动力学异常、炎症损伤、代谢异常等。然而，上述机制并不能充分解释DN的发生发展机制，严格有效的血糖和血压控制可使患者明显获益，但仍有许多糖尿病患者会继发DN，并可进一步发展至CKD甚至ESRF。研究表明，短暂的高糖环境暴露即可活化与DN进展相关的炎症信号分子核转录因子κB(NF-κB)通路，对肾小球系膜细胞功能产生持续的影响[7]。这种影响与表观遗传调控机制改变有关。
2 “代谢记忆”与表观遗传调控机制
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与人们传统认识的基因变异重组引起的遗传改变不同，表观遗传是指在没有基因序列变化的基础上发生的基因表达和随后表型的遗传变化，即基因提供合成生命所需产物的模板序列，而表观遗传机制只对模板序列进行精确调控，使基因组在不同环境条件下选择性表达，从而形成遗传性状。表观遗传调控机制包括DNA甲基化、染色质组蛋白翻译后修饰、非编码RNA(non-coding RNAs，ncRNAs)等。所有这些改变可单独和(或)协同地调控染色质结构及基因表达，从而影响生物体的生理和病理过程。按照基因转录前后区分，将DNA甲基化、组蛋白翻译后修饰等归为选择性转录层面的调控，将ncRNAs归为基因转录后的调控，后者中的微小核糖核酸(miRNA)和长链非编码RNA(lncRNA)对肾脏疾病发展具有重要的调控作用[8]。此外，DNA和组蛋白的各种修饰又被称作表观遗传修饰，由表观基因组编辑酶催化，利用细胞代谢的中间产物[9](如乙酰基和甲基)来修饰组蛋白和DNA，从而调控基因转录。
荟萃分析显示，早期进行血糖强化管理，可使2型糖尿病患者在干预结束后相当长的一段时间内持续获益，称作“遗留效应(legacy effect)”；而早期未进行血糖强化管理的患者，由于存在高血糖刺激，后期虽然接受了强化血糖管理，与早期控制组达到了相似的糖化血红蛋白(HbA1c)控制水平，但其糖尿病并发症仍会继续进展，显示出“代谢记忆(metabolic memory)”现象[10]。研究发现，这种“代谢记忆”现象与机体中的表观遗传改变密切相关[11-12]。高糖等环境状态诱导的表观遗传机制改变，可进一步影响基因表达产物水平。不同条件下的环境刺激可动态影响表观遗传机制，且即使短暂的环境刺激消失，已引起的表观遗传改变仍可持续存在，不会回归到原始水平。上述研究结果提示，早期更好的血糖控制对长期并发症有明显的预防改善作用，代谢紊乱导致的表观遗传改变可能是糖尿病并发症持续进展的根本原因。这种具有延长效应的特性，提示表观遗传调控在DN的发病机制中起着重要作用。因此，由环境刺激导致的持续表观遗传机制改变，可能是有效治疗DN甚至糖尿病并发症的主要障碍。
3 表观遗传修饰对DN的调控作用
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3.1 DNA甲基化
DNA甲基化过程主要由DNA甲基转移酶(DNA methyltransferases，DNMTs)催化[13]，使胞嘧啶-磷酸-鸟嘌呤(cytosine-phosphate-guanine，CpG)二核苷酸的5'-胞嘧啶变成5-甲基胞嘧啶。约60%的人类基因在启动子处有CpG富集——CpG岛，此区域的甲基化常引起基因表达抑制，被称为“沉默”表观遗传标记。而位于基因体的DNA甲基化，有研究提示其与转录延伸即RNA剪接有关[14]。大多数细胞类型均显示出相对稳定的DNA甲基化状态，在正常情况下，仅21.8%的常染色体CpG处于动态调节中，这些处于动态变化的CpG及基因调控元件，尤其是增强子和转录因子结合位点的共定位，可能具有影响转录因子活性的作用[15]。DNA甲基转移酶家族包含DNMT1、DNMT2和DNMT3，其中DNMT3可催化DNA的甲基化，而DNMT1则起着维持甲基化的作用[16]。此外，Ten-eleven-translocation(TET)家族蛋白、胸腺嘧啶DNA糖基化酶(TDG)等可通过抑制DNMTs活性来降低甲基化水平，还可对5-甲基胞嘧啶先后产生氧化、修复作用，从而实现DNA的去甲基化[17-18]。
3.1.1 DN中的DNA甲基化差异
有研究发现，糖尿病肾损害者与无损害者之间存在基因甲基化水平差异，提示部分基因与DN发病有关：Marumo等[19]发现，在糖尿病条件下，肾脏的近端小管细胞DNA甲基化模式及相关基因的表达均发生了明显改变，如血管紧张素原(angiotensinogen，AGT)相关基因的低甲基化及Agt的表达增加。该研究还发现，抑制人肾脏近端小管细胞中的DNMTs，可导致Agt基因启动子区的低甲基化、细胞中AGT蛋白表达水平升高，提示相关基因表达产物水平的变化可继发于靶基因调控区域甲基化状态的改变。TXNIP是一种促氧化和促凋亡相关蛋白，Chen等[11]研究表观基因组图谱时发现，高糖刺激可引起相关基因甲基化程度和TXNIP表达水平的动态变化，而反复高糖刺激造成低甲基化的同时还伴随着基因表达产物的进一步增加。此外，Qiu等[20]发现，在糖尿病状态下，多个与肾功能变化明显相关的甲基化位点定位于富集基因组调控元件区域，可能参与了细胞代谢与凋亡的调控。Sheng等[21]进一步针对血糖、蛋白尿、基线肾功能及eGFR斜率进行了广泛甲基化相关分析(methylation-wide association studies，MWAS)，结果发现DN的不同表型存在差异性甲基化状态，也存在重叠的变化位点，其中血糖控制表型与其他表型重叠最多，提示血糖控制在驱动表观遗传改变方面具有重要作用。
Wing等[22]通过研究慢性肾功能不全患者全血标本中与肾功能下降相关的全基因组DNA甲基化模式发现，肾功能稳定者及快速进展者具有相似的高/低甲基化CpG比例，但肾功能稳定者中80%的CpG位点甲基化程度高于快速进展者，包括NPHP4、IQSEC1和TCF3基因CpG岛的高度甲基化，这些基因参与促进上皮间充质转化的通路，与肾纤维化相关；在快速进展者中仅16%的CpG位点甲基化程度较高；此外，参与氧化应激及炎症的NOS3、NFKBIL2、CLU、NFKBIB、TGF-β3和TGF-β1等基因也存在差异甲基化。该研究结果表明，慢性肾功能不全患者肾功能的迅速丧失可能与甲基化状态对这些基因表达活性的影响有关。
以上研究结果提示，DN患者存在基因甲基化的差异性改变，这种改变可能通过多条途径在DN表型发育中发挥作用，并介导肾脏结构和功能的改变。
3.1.2 DNA甲基化状态对DN的影响
有研究者绘制了健康人及DN患者肾组织全基因组的DNA甲基化图谱，结果显示DN肾组织的差异甲基化高度富集于代谢功能及免疫反应相关基因中[9]。由于启动子区域甲基化改变伴随着基因表达水平的变化，该研究进一步探究了基因调控区域甲基化状态、伴随的基因表达水平变化与肾脏结构及功能改变之间的因果关系，结果显示，甲基化肿瘤坏死因子-α(TNF-α)基因启动子区域可引起相应的RNA水平升高，而TNF-α过表达可导致肾小管上皮细胞损伤和死亡，加重蛋白尿，提示基因调控区域DNA甲基化状态可影响下游基因表达和表型发育，而糖尿病患者肾脏细胞的表观遗传状态改变可直接介导肾脏损伤[9]。Gluck等[23]通过横断面研究发现，DN患者肾小管中存在与肾脏纤维化明显相关的差异性DNA胞嘧啶甲基化，位于基因调控区域的这些甲基化位点可引起邻近基因表达的改变，如最接近γ-干扰素诱导蛋白-16(Gamma-interferon-inducible protein-16，IFI16)转录起始部位的cg20597486探针位点，其低甲基化水平与IFI16表达水平升高及间质纤维化百分比增加相关。此外，还有研究发现，IFI16可激活NF-κB信号通路，通过促进炎症反应和细胞增殖等介导肾组织损害及肾功能下降[24]。
DN的一大特点是肾小球系膜胶原合成增加导致大量细胞外基质堆积，C/EBP同源蛋白(C/EBP homologous protein，CHOP)可通过增加肾组织中胶原相关因子(包括Col1a2、TGF-β1和Col1a4)的表达来促进胶原合成，参与肾脏纤维化。糖尿病患者肾脏组织中的泛素连接酶TRIM13水平降低，并伴随CHOP的表达上调。研究发现，糖尿病肾脏中TRIM13的下降可能与其高甲基化水平有关，而抑制TRIM13启动子甲基化可使TRIM13 mRNA和蛋白水平明显升高，引起CHOP的泛素化及降解，抑制高糖促进的胶原合成，从而改善肾功能[25]。
高血糖状态引起的氧化应激可损伤肾脏，该过程中也存在表观遗传机制的调控。p66Shc适配器蛋白是一种氧化还原酶，可参与线粒体活性氧(ROS)的持续产生及细胞凋亡过程。早在2012年，就有研究观察到高糖条件下p66Shc的过表达可引起ROS持续产生，且血糖恢复正常后p66Shc过表达仍存在，介导持续的高血糖应激反应[26]。在这一过程中伴随着p66Shc基因调控区的低甲基化及染色质组蛋白H3过乙酰化，二者均不随血糖降低而恢复正常。有研究发现，在足细胞中具有抗氧化作用的凝血蛋白酶激活蛋白C(activated protein C，aPC)与其受体结合后可通过阻止p66Shc启动子处CpG的低甲基化及H3的过乙酰化而抑制p66Shc RNA及蛋白的表达，对足细胞产生保护作用[27]。Shahzad等[28]进一步研究发现，高糖刺激可影响DNMT1的活性，而加入aPC可挽救这种活性降低来逆转葡萄糖诱导的CpG低甲基化，提示高血糖环境下DNMT活性下降可造成p66Shc启动子区域的低甲基化，进一步影响下游p66Shc水平，并可能通过PKCβⅡ信号通路及methylglyoxal/AGEs通路来介导氧化应激，导致肾脏损伤[27]。
上述研究表明，糖尿病患者体内存在DNA的甲基化状态改变，主要发生于基因的调控元件区域，通过调控相关基因的表达来介导表型改变。基于这种状态的持续性与可逆性，提示血糖刺激引起的表观遗传调控机制改变可能是传递高血糖损害记忆的关键，从表观遗传调控层面进行干预来改善肾功能可能具有更积极的治疗作用。
3.2 组蛋白翻译后修饰
组蛋白翻译后修饰与DNA甲基化同被称为基因转录前修饰，可单独和(或)协同控制基因的表达。组蛋白(1个H3-H4四聚体和2个H2A-H2B二聚体构成的八聚体结构)与包绕其上的DNA共同组成的核小体是遗传物质染色质的单位结构。在组蛋白氨基酸修饰中起催化作用的有组蛋白乙酰转移酶(histone acetyltransferases，HAT)、组蛋白甲基转移酶(histone methyltransferases，HMT)，以及与之对应的组蛋白去乙酰化酶(histone deacetylases，HDAC)、组蛋白去甲基化酶(histone demethylases，HDM)等，可动态修饰组蛋白八聚体结构上的裸露氨基酸残基(如赖氨酸和精氨酸)。目前，在已探索的60多种组蛋白修饰中，对乙酰基化和甲基化的研究最为深入。除直接影响染色质结构外，组蛋白修饰还可通过募集效应蛋白、干扰重塑复合物等方式间接发挥调节作用[29-30]。有研究发现，赖氨酸或精氨酸残基上的甲基化和乙酰基化是调控肾脏发育和疾病过程中基因表达的关键表观遗传机制[31]。
3.2.1 高糖状态下组蛋白过度乙酰化对DN的影响
组蛋白赖氨酸的乙酰化或过乙酰化通常可致转录激活。Miao等[12]对糖尿病血管并发症进行表观遗传研究发现，患者血单核细胞中H3K9乙酰化(H3K9Ac)水平与HbA1c控制水平明显相关，且合并视网膜病变或肾病时，单核细胞中存在更多的启动子H3K9Ac，它们主要富集于与糖尿病并发症相关的基因中，尤其是炎症相关的NF-κB通路。高糖条件下的血管炎症可能是由长期过度乙酰化介导的，而持续的炎症则进一步造成了肾脏相关的损害。
介导血管炎症的表观遗传变化不仅存在于血循环的单核细胞中，还可能存在于糖尿病患者的肾组织中，直接参与肾脏的结构及功能损害。有研究发现，在DN患者肾活检组织中，高糖可导致足细胞中Notch1和Notch4启动子H3K9Ac水平升高，并激活Notch信号通路，后者可参与蛋白尿的形成及肾小球硬化[32]。过表达高度特异性的去乙酰化酶SIRT6，可使H3K9去乙酰化而抑制Notch信号通路，并降低Notch信号下游靶基因如HES1和Snail1的表达，减轻炎症反应、减少细胞凋亡，从而产生足细胞保护作用，改善蛋白尿。烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide，NAD+)调节的去乙酰化酶SIRT1过表达也可改善蛋白尿，对肾脏产生保护作用。Hasegawa等[33]发现，在糖尿病早期，近端小管中就已经出现了Sirt1蛋白水平的降低，随后引起肾小球Sirt1蛋白水平降低、Claudin-1蛋白水平升高，最终导致蛋白尿。此外，足细胞中H3的过度乙酰化可激活p66Shc，使足细胞中线粒体相关的ROS持续产生，从而导致氧化应激反应，促进肾脏损伤[27]。
Wang等[34]发现，糖尿病条件下，氨基末端激酶(C-jun N-terminal kinase，JNK)通路的活化可使肾小球增大，并发生肾纤维化，促进肾脏损害。该通路对肾脏损害的机制也与表观遗传改变有关，JNK通路激活可上调组蛋白乙酰化酶P300/CREB结合蛋白(cAMP response element binding protein，CBP)的表达，促进组蛋白H3K9/14乙酰化，增强CTGF、PAI-1和FN-1基因的表达，最终使肾纤维化和肾小球硬化加重，而抑制JNK信号及下调P300可降低组蛋白乙酰化水平。Wang等[34]利用HAT抑制剂姜黄素的类似物C66及JNK酶抑制剂抑制JNK通路活化，结果显示其可有效预防糖尿病诱导的肾脏纤维化和功能障碍，即使停止治疗后对JNK信号的抑制作用消失，且在6个月的随访时间内HAT酶活性持续减弱，但肾脏保护作用依然持续存在，提示表观遗传调控层面的有效干预最终可达到持续的治疗效果。
3.2.2 高糖状态下组蛋白甲基化状态对DN的影响
组蛋白赖氨酸和精氨酸残基甲基化最常见，包括单甲基、二甲基或三甲基修饰，而组蛋白裸露氨基酸甲基化修饰介导的基因激活或抑制功能由甲基化程度及不同的修饰残基决定。
组蛋白上的赖氨酸残基甲基化可影响DN的进展。Suv39H1是一种HMT，可催化组蛋白H3赖氨酸9三甲基化(H3K9me3)。在高糖条件下，磷脂酰肌醇3激酶(phosphoinositide 3-kinase，PI3K)和JNK通路活化，可使小鼠系膜细胞中的Suv39h1酶及H3K9甲基化水平降低，而纤连蛋白及p21蛋白表达水平升高[35]。Suv39h1过表达可恢复H3K9甲基化水平，减少高糖诱导的纤维连接蛋白和p21表达，预防系膜细胞肥大，并可部分逆转高糖引起的人肾脏炎症和细胞凋亡[36]。Li等[37]发现，糖尿病小鼠肾小球P21基因表达上调，同时其启动子区域的H3K4me1和H3K4me3水平明显升高，而TGF-β1抗体可直接干扰P21基因启动子处HMT SET7/9的募集及H3K4甲基化，从而调控P21 mRNA的表达，证实了TGF-β1抗体在表观调控层面对DN的预防作用。
转录因子Pax6启动子处甲基化水平降低可增加TXNIP的表达，促进足细胞的氧化应激和程序性死亡；而HMT zeste同源物2增强子(enhancer of zeste homolog 2，EZH 2)可上调Pax6甲基化水平，从而对足细胞产生保护作用[38]。Majumder等[39]也发现，HMT EZH 2缺失会加重小鼠肾小球疾病易感性，而抑制HDM、上调H3K27me3水平则可减轻肾脏损伤。该研究还发现，足细胞H3K27me3水平下降可激活Notch通路，因而更易发生局灶节段性肾小球硬化。值得注意的是，人类肾疾病中也存在相似的改变。Majumder等[39]还发现，DN患者肾脏组织的足细胞中H3K27me3水平降低，HDM UTX表达水平升高，且伴有肾小球硬化者细胞核中H3K27me3总体水平明显降低，提示肾组织中的H3K27me3可能是一种保护性标记。
高糖刺激的T X N I P基因活化过程中，H3K27me3的甲基化水平降低，同时存在H3K9ac、H3K4me1和H3K4me3水平升高，且后三者与TXNIP mRNA的变化呈正相关，提示葡萄糖可影响表观遗传修饰的基因激活/抑制作用[40]。此外，与糖尿病发病密切相关的OPN基因表达上调与基因活性标记H3K9Ac、H3K4me1和H3K4me3水平升高及基因抑制标记H3K27me3水平降低也密切相关[41]。这些研究结果均提示葡萄糖可能是基因表达开关的强诱导剂，揭示了早期强化血糖管理有益于糖尿病患者的原因。总之，针对组蛋白修饰的表观遗传机制干预可能是一种保护肾脏的有效治疗方式。
3.3 基于表观遗传调控的临床治疗
识别和结合组蛋白中翻译后修饰或未经修饰区域的蛋白质被称为“表观遗传读者(epigenetic reader)”。这些蛋白质通常依赖特定的结构域，包括甲基赖氨酸或乙酰赖氨酸染色质结构域、PHD finger结构域、溴区结构域(bromodomain，BD)等。因此，某一特定表观修饰的功能结果还取决于在特定的生物学背景下识别它的读取器蛋白。“reader”溴域和末端外(bromodomain and extra terminal，BET)蛋白家族通常与乙酰化赖氨酸残基结合来调控基因转录，针对这一结构域的BET蛋白抑制剂可通过调控细胞增殖、炎症和免疫反应发挥作用，在肿瘤临床治疗方面具有良好的应用价值[42]。在表观遗传层面治疗的临床试验中，有研究发现，BET蛋白BD2选择性抑制剂阿帕他龙(apabetalone)可有效改善糖尿病患者的肾功能[43]。此外，有研究发现，糖尿病治疗的热点钠/葡萄糖协同转运蛋白2(SGLT2)抑制剂的调控机制也与表观遗传改变有关，SGLT2抑制剂可增加循环和组织中的3-羟基丁酸水平，并诱导脂肪细胞中组蛋白H3K9的β-羟基丁基化修饰，从而发挥心血管保护作用[44-45]。
3.4 表观遗传修饰的协同作用
Chen等[11]发现，反复高糖刺激后，后续的甲基化更加明显，且可使相关基因表达水平更高，提示前期的表观遗传变化可能易化后续刺激的影响。Marumo等[19]发现，Agt基因的去甲基化与组蛋白修饰改变具有时序性，且抑制DNMTs或HDACs均可上调人近端小管细胞中Agt mRNA的表达。该研究结果显示，近端小管细胞中Agt去甲基化在第5周(血糖水平和体重刚开始增加)时不明显，在第8周时则非常明显，而Agt启动子的H3K9Ac水平在第5、8周时均升高，H3K4me3水平则在第8周时升高，提示糖尿病肾脏表观遗传改变是从H3K9乙酰化开始，再逐渐扩展到H3K4三甲基化和DNA去甲基化的。此外，SIRT1介导的肾脏保护过程中，也存在组蛋白翻译后修饰和DNA甲基化状态改变，且SIRT1过表达可引起组蛋白H3和H4的去乙酰化，增强CpG区域H3K9的二甲基化，而组蛋白去乙酰化诱导的组蛋白甲基化可导致DNMTs的募集，其中DNMT1的募集可使Claudin-1基因的甲基化水平升高，并下调足细胞中Claudin-1的表达，从而使蛋白尿减轻[33]。以上研究结果均提示，表观遗传机制长期稳定存在的原因可能与表观遗传修饰之间存在协同与自稳作用有关，这也进一步提示了早期且长期血糖强化控制的重要意义。
3.5 表观遗传修饰的应用价值
在以往的DN风险预测模型中，基线eGFR、蛋白尿等血液生化指标被用于预测肾功能下降；而Qiu等[20]的研究则提示，多个与eGFR斜率明显相关的甲基化位点可用于预测肾功能下降；此外，还有研究发现，DNA甲基化改变也可改进肾功能下降预测模型的性能[23]。与传统的预测指标相比，表观遗传机制具有持续性、动态和可逆性，且不受常规糖尿病治疗的影响，具有良好的预测价值[19]。
有学者对DN的不同组织类型进行表观遗传特征研究，结果在糖尿病患者尿液、唾液、循环血液及肾组织中均发现了表观遗传机制的差异性改变[46]。糖尿病早期尚未发展至DN时，在肾脏中即可检测到引起表观遗传机制改变的分子变化，而当发展为DN后，机体的血液细胞中也可检测到相关表观遗传的分子改变[12，33]。在血液中检测到与肾功能下降相关的甲基化位点，此时如行肾脏组织检测，则可发现其甲基化水平与肾脏纤维化的相关性[20]，提示全血中与肾功能相关的甲基化差异可能是由肾脏疾病引起的[47]，而血液样本的采集较肾组织穿刺的侵入性小，更易于被接受，因而可作为肾穿刺前的先验检查手段。
4 总结与展望
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DN是糖尿病的一种肾脏慢性血管并发症，也是CKD和ESRF最常见的病因。尽管有大量的临床需求，但目前对于DN的治疗仍主要依靠血糖控制及改善血压等方法。DN的病理特征是大量细胞外基质、纤维胶原和炎症细胞的堆积。DNA甲基化、组蛋白翻译后修饰作为基因转录前的表观遗传修饰，可通过调控基因表达从多种信号途径来加重肾小球足细胞及肾小管上皮细胞的损伤，促进肾脏组织中的病态氧化应激及炎性反应等病理生理改变，介导DN的进展。对糖尿病状态下存在的表观遗传机制相关记忆现象的研究，提出了不同于传统靶向治疗的思路。针对表观遗传调控层面上的干预，可能会更有效地延缓肾脏疾病进展，并改善患者的糖尿病并发症及预后。但目前针对表观遗传调控机制的研究及临床转化主要集中在血液肿瘤方面，而对糖尿病相关并发症的研究仍较少，需要进一步关注与探索。
基金
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  • 国家自然科学基金(82170736)
  • 国家自然科学基金(81970629)
文献
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2023年第48卷第7期
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doi: 10.11855/j.issn.0577-7402.2952.2022.1124
  • 接收时间：2021-12-24
  • 首发时间：2025-12-03
  • 出版时间：2023-07-28
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  • 收稿日期：2021-12-24
  • 录用日期：2022-08-31
基金
National Natural Science Foundation of China(82170736)
国家自然科学基金(82170736)
National Natural Science Foundation of China(81970629)
国家自然科学基金(81970629)
作者信息
    1东南大学附属中大医院肾内科，江苏南京 210009
    2浙江大学附属第二医院肾脏内科，浙江杭州 310000

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
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