药学学报

	LncRNA	Description	Suggested function	Reference
Diabetic nephropathy	TUG1	Recruits PGC-1α to promoter and serves as a sponge for miR-377	miRNA binding/protein binding/transcriptional activation	[20, 27]
NEAT1	Activates the AKT/mTOR signal and serves as a sponge for miR-27b-3p	miRNA binding/expression changed	[21, 32]
MALAT1	Associated with podocyte damage and involve in inflammatory processes	miRNA binding/expression changed	[22, 25, 26]
PVT1	Serves as a host of miRNA 1207-5p and regulates ECM formation	Expression changed	[23, 28-31]
Lnc-MGC	Harbors 40 miRNAs and regulated by endoplasmic reticulum stress signal	miRNA binding	[24]
CYPB1-PS1-001	Downregulated in early phases of DN	Protein binding	[33, 34]
LINC01619	Induces oxidative podocyte damage by serving as a sponge for miR-27a	miRNA binding	[35]
Gm6135	Impair miR-203-3p and downregulate of TLR4	miRNA binding	[36]
1700020I14Rik	Reduces cellular proliferation via inhibition of miR-34-a-5p	miRNA binding	[37]
150Rik	Promotes proliferation by sponging miR-451	miRNA binding	[38]
H19	Induces miR-675 and modulates vitamin D receptor expression	Transcriptional activation	[39]
ERBB4-IR	Suppresses miR-29b and serves as target gene of smad3	Transcriptional repression	[40, 41]
ZEB1-AS1	Enhances ZEB1 by promoting H3K4me3 histone modification	Recruitment of histone modifications	[42]
Focal segmental glomerulosclerosis	LOC105375913	Increases in tubular cells and induced by the C3a/p38/XBP-1s pathway	miRNA binding	[46]
LOC105374325	Serves as a sponge for miR-34c and miR-196a/b	miRNA binding	[47]
Membranous nephropathy	Xist, NEAT1	Sequestrate miR-217 and upregulate of TLR4	miRNA binding	[48, 49]
Lupus nephritis	RP11-2B6.2	Inhibits SOCS1and increases the IFN-1 signaling pathway	Epigenetic inhibition	[50]
LINC0949, LINC0597	Participate in the synthesis of pro-inflammatory factors	Unknown	[51]

	LncRNA	Description	Suggested function	Reference
Diabetic nephropathy	TUG1	Recruits PGC-1α to promoter and serves as a sponge for miR-377	miRNA binding/protein binding/transcriptional activation	[20, 27]
NEAT1	Activates the AKT/mTOR signal and serves as a sponge for miR-27b-3p	miRNA binding/expression changed	[21, 32]
MALAT1	Associated with podocyte damage and involve in inflammatory processes	miRNA binding/expression changed	[22, 25, 26]
PVT1	Serves as a host of miRNA 1207-5p and regulates ECM formation	Expression changed	[23, 28-31]
Lnc-MGC	Harbors 40 miRNAs and regulated by endoplasmic reticulum stress signal	miRNA binding	[24]
CYPB1-PS1-001	Downregulated in early phases of DN	Protein binding	[33, 34]
LINC01619	Induces oxidative podocyte damage by serving as a sponge for miR-27a	miRNA binding	[35]
Gm6135	Impair miR-203-3p and downregulate of TLR4	miRNA binding	[36]
1700020I14Rik	Reduces cellular proliferation via inhibition of miR-34-a-5p	miRNA binding	[37]
150Rik	Promotes proliferation by sponging miR-451	miRNA binding	[38]
H19	Induces miR-675 and modulates vitamin D receptor expression	Transcriptional activation	[39]
ERBB4-IR	Suppresses miR-29b and serves as target gene of smad3	Transcriptional repression	[40, 41]
ZEB1-AS1	Enhances ZEB1 by promoting H3K4me3 histone modification	Recruitment of histone modifications	[42]
Focal segmental glomerulosclerosis	LOC105375913	Increases in tubular cells and induced by the C3a/p38/XBP-1s pathway	miRNA binding	[46]
LOC105374325	Serves as a sponge for miR-34c and miR-196a/b	miRNA binding	[47]
Membranous nephropathy	Xist, NEAT1	Sequestrate miR-217 and upregulate of TLR4	miRNA binding	[48, 49]
Lupus nephritis	RP11-2B6.2	Inhibits SOCS1and increases the IFN-1 signaling pathway	Epigenetic inhibition	[50]
LINC0949, LINC0597	Participate in the synthesis of pro-inflammatory factors	Unknown	[51]

LncRNA与慢性肾脏病的研究进展

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王伟达 , 李昭君 , 陈园园 , 陈晓光 , 张森 ^*

药学学报 | 综述 2019,54(11): 1918-1925

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药学学报 |综述 2019 , 54 (11) : 1918 -1925

LncRNA与慢性肾脏病的研究进展

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王伟达, 李昭君, 陈园园, 陈晓光, 张森^*

作者信息

中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

*张森, Tel: 86-10-63165207, E-mail: zhangs@imm.ac.cn; chxg@imm.ac.cn

Recent advances in LncRNAs and chronic kidney disease

Wei-da WANG, Zhao-jun LI, Yuan-yuan CHEN, Xiao-guang CHEN, Sen ZHANG^*

Affiliations

Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2019-11-12 doi: 10.16438/j.0513-4870.2019-0464

文章导航

摘要

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长链非编码RNA（long noncoding RNA，LncRNA）是一类不具备或较少具备编码能力的转录本。近年来，这些曾被认为是基因转录组“噪音”的LncRNA受到了极大的关注，并正成为生物调节中潜在的重要参与者。LncRNA具有广泛的生物学功能，其异常表达与癌症、免疫疾病和代谢疾病等多种疾病相关。慢性肾脏病（chronic kidney disease，CKD）在全球不同地区的发病率为10%~15%，具有增长率高、不知晓率高的特点。主要有糖尿病肾病、膜性肾病以及各种免疫介导的肾小球疾病。现在已有不少研究证据表明，LncRNA与肾脏有着密切的联系，或许可成为新的治疗靶点或新的生物标志物来诊断疾病的发生发展。本文将对LncRNA的功能以及LncRNA与各种慢性肾脏疾病的现有研究做一总结，并展望了LncRNA在治疗CKD方面临床应用的前景。

关键词

长链非编码RNA / 糖尿病肾病 / 膜性肾病 / 狼疮性肾炎 / IgA肾炎 / 慢性肾脏病

Abstract

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Long non-coding RNAs (LncRNAs), defined as transcripts which are hundreds of nucleotides with little or non-protein coding potential. Recently, LncRNAs have caught much more attentions, instead of considering as noises of genome transcripts, and indeed they have been found to play important roles associated with some biological processes, such as tumorigenesis, immunology dysfunction, metabolism adjustment, and so on. The incidence of chronic kidney disease (CKD) in different regions of the world is about 10% to 15%, with high growth rate and high unawareness, including the diabetic nephropathy, membranous nephropathy, etc. Previous publications also suggest that LncRNAs have a close relationship with the kidneys, and it may become new therapeutic targets or new biomarkers to diagnose diseases. In this review, we will summarize LncRNAs' functions with chronic kidney diseases, and discuss the prospects of the clinical applications of LncRNAs in the treatment of CKD treatment.

Key words

long non-coding RNA / diabetic nephropathy / membranous nephropathy / lupus nephritis / IgA glomerulonephritis / chronic kidney disease

引用本文

王伟达, 李昭君, 陈园园, 陈晓光, 张森. LncRNA与慢性肾脏病的研究进展. 药学学报, 2019 , 54 (11) : 1918 -1925 . DOI: 10.16438/j.0513-4870.2019-0464

Wei-da WANG, Zhao-jun LI, Yuan-yuan CHEN, Xiao-guang CHEN, Sen ZHANG. Recent advances in LncRNAs and chronic kidney disease[J]. Acta Pharmaceutica Sinica, 2019 , 54 (11) : 1918 -1925 . DOI: 10.16438/j.0513-4870.2019-0464

正文

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1 LncRNA定义

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LncRNA被定义为长度超过200个核苷酸但没有蛋白编码能力的RNA分子, 最初被认为是转录中的“噪音”, 不具备功能或具有很少功能^[1], 但随着对人类全基因组研究的不断深入, LncRNA的定义也不断被丰富。在人类基因组中, 有超过70%的基因可以进行转录, 而非编码RNA几乎占据了可转录基因的全部(只有大约2%的编码RNA), LncRNA是非编码RNA中数量庞大的一部分, 另外还包括一些核糖体RNA (rRNA)、转运RNA (tRNA)、microRNA等^[2]。LncRNA与信使RNA (mRNA)相似, 通过RNA聚合酶Ⅱ转录产生^[3], 大部分都有5'端加帽和3'端多腺苷酸化。但与mRNA相比, LncRNA不具备编码功能, 而且它的表达水平较低, 在不同种属之间的保守性也差^[4], 但LncRNA有着独特的组织特异性和细胞特异性, 而且数量是mRNA的3~100倍。LncRNA与mRNA相比, 更多地富集在细胞核中, 但LncRNA作为一类RNA在细胞质中也较为丰富^[5]。

2 LncRNA分类与功能

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根据LncRNA编码序列与蛋白质编码基因的相对位置可分为以下6类^[6]:正义sense-lncRNA、反义antisense-lncRNA、双向bidirectional-lncRNA、内含子intronic-lncRNA、基因间intergenic-lncRNA和增强子enhancer-lncRNA。顾名思义, sense-lncRNA和antisense-lncRNA是指LncRNA序列与蛋白质编码基因的正义链或者反义链重叠; Bidirectional-lncRNA是指LncRNA序列位于距蛋白质编码基因的相反链; Intronic-lncRNA是指LncRNA序列全部来自另一个转录物的内含子; Intergenic-lncRNA是指不位于任何其他蛋白质编码基因座附近的LncRNA; Enhancer-lncRNA是指LncRNA转录自蛋白编码基因的增强子区域; 虽然相对位置确定, 但是这些LncRNA的功能在很大程度上都是未知的。

LncRNA在表观遗传调控、细胞周期调控和细胞分化调控等众多生命活动中发挥重要作用, 与包括癌症在内的多种疾病息息相关, 因此成为生命科学领域的研究热点^[7]。RNA不仅仅扮演着遗传信息中间载体的辅助性角色, 并且承担了各种调控功能。LncRNA发挥生物学功能主要依靠其二级结构或三级结构, 它可以与蛋白质结合, 引起染色质重构或调控转录因子, 还可以与microRNA结合, 间接影响mRNA表达; 也可以直接与mRNA结合, 影响mRNA翻译、剪切和降解过程^[8]。LncRNA在基因表达中发挥的复杂精确的调控功能, 极大地解释了基因组复杂性的难题, 同时也使得人们从基因表达调控网络的维度来认识生命体的复杂性, 开启生命科学新天地。但是目前对LncRNA的认知可以说还处于初级阶段, 还有许多未知需要探索。本文首先重点介绍LncRNA的功能。

2.1 表观遗传学调控

LncRNA是一种新兴的表观遗传调控分子, 某些特异的LncRNA会招募染色质或复合体到特定位点, 改变DNA或者RNA甲基化状态以及染色体的结构和修饰状态, 进而调控相关基因的表达。

2.2 转录调控

转录过程中, 一些LncRNA可以作为配基, 与特定的转录因子结合, 形成复合体, 从而控制基因转录。或者直接与DNA或者蛋白质结合来调控转录; Postepska-Igielska等^[9]认为LncRNA Khps1能够通过激活鞘氨醇激酶1 (sphingosine kinase 1, SPHK1)的启动子调控原癌基因的表达。在这个过程中, Khps1与SPHK1通过RNA-DNA绑定的方式, 诱导染色质修饰酶形成疏松的结构, 利于E2F1转录因子的接近, 诱导下游信号通路改变。

2.3 转录后调控

LncRNA还会直接参与转录后调控过程, 包括可变剪切、RNA编辑、蛋白翻译及转运等。Lin等^[10]在小鼠胚胎干细胞的研究中发现, Tcl1上游的神经相关的lincRNA (Tcl1 upstream neuron-associated lincRNA, lincRNA TUNA)可与核仁素、聚嘧啶束结合蛋白等结合形成多聚物, 影响神经分化。TUNA与多种蛋白结合形成的多聚物通过与干细胞神经分化相关基因的启动子区域结合, 促进基因转录, 参与干细胞神经分化多能性的调控, 敲低TUNA会抑制神经分化。

2.4 调控microRNA

除了直接调控mRNA, LncRNA还能通过控制microRNA表达来上调或下调其靶基因的表达量。在一些肿瘤细胞和特定组织中, 一些LncRNA会携带有某些miRNA的“种子序列”, 可以像“海绵”一样结合miRNA, 从而阻止miRNA同其靶mRNA结合。

2.5 其他调节方式

LncRNA还可以直接与相应的蛋白结合, 调控蛋白的活性。Wang等^[11]在树突状细胞(DCs)中发现了特征性表达的Lnc-DC, 敲低Lnc-DC可抑制DC的分化, 降低DC对T细胞激活的能力。Lnc-DC可与信号转导及转录激活蛋白3 (signal transducer and activator of transcription 3, STAT3)蛋白结合, 影响其与SHP1的结合, 使其免于去磷酸化, 从而激活转录。

3 LncRNA的作用模式

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LncRNA按照作用模式可以分为4大类:信号(signal)、诱饵(decoy)、引导(guide)和支架(scaffold)^[12]。

3.1 信号

LncRNA的第一种作用是作为“信号”调控下游基因转录。已有的研究发现, 在不同的刺激条件和信号通路下, LncRNA将会被特异性地转录, 并作为信号传导分子, 参与特殊信号通路的传导。一些LncRNA被转录后, 便拥有了调控下游基因转录的作用。就生物体的角度而言, 利用RNA进行转录调控是具有明显优势的, 因为此过程不涉及蛋白质的翻译, 因此具有更好的反应速度, 对于机体的某些急性反应可以做出更迅速的回应。如LncRNA可以直接结合到染色体中邻近位置的DNA上, 调节基因表达, 即顺式调控模式(cis-regulation)。Pandey等^[13]发现Kcnq1ot1在不同的发育条件或者刺激下会被转录, 从而影响下游信号传导, 该过程具有组织特异性和阶段依赖性。Kcnq1ot1通过调节钾离子电压门控通道q1 (potassium voltage-gated channel subfamily q member 1, Kcnq1)的印迹控制区的沉默功能来控制Kcnq1表达。

3.2 诱饵

LncRNA的第二种作用是分子阻断剂。此类LncRNA被转录后直接与相应的蛋白(如转移因子/转录调节子)结合, 从而阻断了该分子的作用和信号通路。如肺腺癌转移相关转录物1 (metastasis associated lung adenocarcinoma transcript 1, MALAT1)和肌球蛋白重链相关RNA转录本(myosin heavy-chain-associated RNA transcripts, MHRT)可以通过在染色质中螯合转录因子和其他蛋白来抑制转录。其中, MALAT1在核散斑域中隔离丝氨酸/精氨酸(SR)剪接因子, 从而调节可变剪接^[14]。MHRT通过影响染色质阻遏复合体控制染色质重塑的能力, 来调节参与心脏收缩性的相关基因的表达^[15]。

3.3 引导

第三种作用模式是引导。LncRNA可以通过结合蛋白质(如染色质修饰剂)诱导基因表达的变化, 并将得到的核糖核蛋白复合物导向染色质和其他特异性靶标。在这一过程中它们以顺式或反式作用, 诱导基因表达的变化。如位于转录因子编码基因Foxf1附近的, 与发育调控相关的LncRNA-Fendrr, 它与多梳家族蛋白2 (PRC2)相互作用, 之后形成的结构复合物与Foxf1的启动子区域结合并且配对类同源域转录因子2 (Pitx2), 从而导致这两个基因的沉默^[16]。

3.4 支架

LncRNA还可以起到一个“中心平台”的作用, 即多个相关的转录因子或者miRNA都可以结合在这个LncRNA分子上。支架LncRNA可以结合多个相互作用配体, 当单独起作用时可能各自均衡地调节转录并导致转录抑制或激活。支架LncRNA的丢失可能导致无法组装不同的相互作用的配体, 这可能导致配体的功能丧失。INK4基因座CDKN2B-AS1 (也称为ANRIL)中的反义LncRNA就是一个这样的例子。CDKN2B-AS1可以同时结合多梳家族蛋白1 (PRC1)和PRC2, 并诱导INK4b-ARF-INK4a基因座的沉默^[17]。

LncRNA的作用模式可以总结为以上4种, 但这4种作用机制是相互关联的, 因此不能把LncRNA的功能孤立来看, 要从整体的角度更好地理解lncRNA的机制。

4 LncRNA与肾脏疾病的关系

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LncRNA在肾脏中的研究, 不像在免疫或者肿瘤中发展的那么成熟, 相关的报道也较少。很多LncRNA的功能和机制都没有阐述清楚, 不过随着技术的不断发展和研究投入的不断增加, 有关LncRNA与各种肾脏疾病的关系将逐渐得到阐明。慢性肾脏疾病主要包括糖尿病肾病、局灶性节段性肾小球硬化、膜性肾病、狼疮性肾炎和IgA肾病。本文将针对目前已经报道的文献, 对这5种慢性肾病相关的LncRNA做一总结分析, 其中糖尿病肾病相关报道较多, 其次为局灶性节段性肾小球硬化以及膜性肾病, 按照其的分子功能将相关LncRNA分类, 如图 1所示。

4.1 糖尿病肾病

现阶段LncRNA与糖尿病肾病(diabetic nephropathy, DN)的研究较多。DN是最常见的糖尿病微血管并发症之一, 其终末期表现为肾组织纤维化, 最终导致肾衰竭^[18]。DN的确切发病机制尚不清楚, 随着对LncRNA的不断深入了解, 越来越多的研究明确了LncRNA在DN发生发展中扮演的角色。目前有关DN的LncRNA有很多都在其他疾病中被报道过, 在DN中大部分研究都集中在这些LncRNA和miRNA相互作用的关系上, 虽然miRNA不是本篇综述的重点, 但DN中的LncRNA和miRNA相互作用的复杂关系还是十分重要的。如前文所述, LncRNA可以影响miRNA的功能, 如作为吸附miRNA的“海绵”, 阻止miRNA与相应的靶mRNA结合^[19], 包括牛磺酸上调基因1 (taurine upregulated gene1, TUG1)、富含核富集的转录物1 (nuclear enriched abundant transcript 1, NEAT1)和MALAT1^[20-22]; LncRNA还可以携带经过转录后修饰而释放的miRNA来发挥功能, 其中主要的例子是LncRNA浆细胞瘤变体异位基因1 (plasmacytoma variant translocation 1, PVT1)^[23]。

Kato等^[24]发现Lnc-MGC在DN模型小鼠的肾小球中上调, 在体外高糖模型中也显著增加。通过研究发现, Lnc-MGC可以作为近40个miRNA的“支架”, 并受内质网应激相关转录因子CHOP调控。在糖尿病Chop^-/-小鼠中, 簇状miRNA和Lnc-MGC表达降低, 抑制Lnc-MGC的表达显示出对DN的保护作用。目前已有一种靶向Lnc-MGC的化学修饰寡核苷酸, 它可以抑制糖尿病小鼠的团簇的miRNA并使肾小球细胞外基质(extra cellular matrix, ECM)和肾小球肥大情况减轻, 说明了靶向Lnc-MGC对控制DN进展的重要意义。

MALAT1是参与DN中LncRNA的另一个重要例子。MALAT1在链脲佐菌素诱导的DN小鼠模型中被发现。Hu等^[25]发现MALAT1在体外高糖刺激的足细胞损伤模型中也发挥作用, 其中主要机制是MALAT1结合蛋白SPSF1参与了beta-catenin通路的调控。此外, MALAT1还参与了DN中其他肾脏细胞类型的损伤。MALAT1在高糖刺激下导致TNF-α和IL-1水平上调, 提示MALAT1参与了内皮的炎症过程^[26]。在肾小管上皮细胞中, 高糖诱导下的MALAT1通过靶向miR-23c并连续上调ELAVL1和NLRP3, 导致细胞的焦亡增加^[22]。

线粒体功能障碍是DN的标志之一。通过2016年的一项重要研究发现, 线粒体代谢的调节与LncRNA TUG1相关^[27]。Long等^[27]发现LncRNA-TUG1是在足细胞上特异表达的LncRNA, 它可以通过与转录共激活因子PGC-1α的上游TUG1结合元件结合, 调节足细胞中线粒体的生物功能。TUG1表达下调使线粒体与生物能量相关的靶基因表达水平下降, 导致线粒体功能紊乱, 触发DN的发生。Duan等^[20]还发现, miR-377在高糖刺激肾小球系膜细胞的时候表达上调, 并可以抑制过氧化物酶体增殖剂激活受体(peroxisome proliferators-activated receptors, PPAR) γ, 促进转化生长因子-β1 (transforming growth factor-β1, TGF-β1)和纤溶酶原激活物抑制因子-1 (plasminogen activator inhibitor-1, PAI-1)的表达, 加速ECM的积聚, 而TUG1可以拮抗miR-377的作用, 减少ECM在肾小球系膜细胞内的积聚。

PVT1是第一个被证实与肾脏疾病相关的LncRNA, 后来被证实与DN的发生相关^[28]; PVT1的变异与1型和2型糖尿病患者发展至终末期肾衰竭(end-stage renal disease, ESRD)相关^[29]。在高糖环境下, 系膜细胞中此基因的表达会上调。敲除PVT1显着降低了ECM相关蛋白及其转录调节因子PAI-1和TGFβ1的上调, 证实了该基因与DN发病机制之间的功能联系^[30]。PVT1的分子机制如前文所述, 它可携带几种miRNA, 其中一种miR-1207-5p可以与PVT1共同调节ECM的形成^[23]。Zhang等^[31]以中药当归补血汤为主要成分, 通过靶向PVT1, 进一步证实了PVT1抑制了高糖刺激下肾小球系膜细胞的增殖和ECM形成。

此外, 报道表明LncRNA NEAT1在DN中也起到了重要的作用。在链脲佐菌素介导的糖尿病大鼠模型和用高糖处理的小鼠系膜细胞中都诱导表达了NEAT1^{[21, 32]}。NEAT1表达增加导致AKT/mTOR信号通路的激活, 同时伴有细胞增殖和纤维化^[32]。有趣的是, 这种病理状态可以通过敲除NEAT1来缓解, 提供了治疗的前瞻性。此外, NEAT1也充当了miR-27b-3p的“海绵”, 减轻了锌指增强子区结合同源框1 (zinc-finger E-box-binding homeobox 1, ZEB1)的抑制作用, ZEB1是一种锌指转录因子, 与上皮-间充质转化和ECM沉积相关^[21]。

CYP4B1-PS1-001是一个首次在DN中被描述的LncRNA, 是通过糖尿病小鼠模型中的基因芯片筛选得到的^[33]。这个LncRNA在DN的早期阶段被显著下调, 而过表达它可以缓解系膜细胞的增殖。CYP4B1-PS1-001的这种作用可能是由核仁中的核蛋白酶体降解介导的。CYP4B1-PS1-001和CYP4A12A通过影响肾小球系膜细胞的增殖和纤维化从而参与调节DN的进展^[34]。

除了以上这些“明星分子”外, 还有很多LncRNA都在DN疾病的进展中发挥了重要的生物学功能。据目前报道, 与DN相关的LncRNA有20多条, 除上文所述, 还有一些其他的LncRNA也是直接与miRNA相互作用并抑制其功能。以足突细胞损伤为例, LINC01619作为miR-27a的“海绵”诱导足细胞损伤^[35]; Gm6135通过抑制miR-203-3p介导的TLR4下调, 保护细胞免受增殖和凋亡^[36]; lincRNA1700020I14Rik通过抑制miR-34-a-5p来抑制细胞增殖, LncRNA 150Rik通过作为miR-451的“海绵”, 来促进细胞增殖^{[37, 38]}。除了直接抑制miRNA的功能外, LncRNA H19通过诱导miR-675来调节维生素D受体的表达^[39], LncRNA Erbb4-IR通过在转录水平上抑制miR-29b来影响DN的发展。其中, Erbb4-IR可以作为Smad3的靶基因, 通过TGF-β/Smad通路影响肾脏的纤维化等。它可作为“诱饵”来抑制抗纤维化的miR-29b, 促进肾脏纤维化过程, 是研究DN与LncRNA关系的经典的例子^[40]。其他研究发现, LncRNA还可以通过调节表观遗传修饰来调控疾病的发生发展^[41]。LncRNA ZEB1-AS1在高糖刺激下, 可以通过促进其启动子上的H3K4me3组蛋白修饰来增强ZEB1的表达, 增加ZEB1的抗纤维化作用^[42]。

虽然大部分数据主要是在小鼠或大鼠模型中获得的, 但是有很多LncRNA, 尤其在DN中发现的LncRNA, 大多已经被发现它们在进化中具有保守性, 这表明在人类基因的数据库中也有这些LncRNA的存在并发挥相应的作用^[43-45], 意味着在动物模型中获得的数据在今后可以用于临床的研究。

4.2 局灶性节段性肾小球硬化

与DN相比, 对于其他慢性肾病来说, 人们对LncRNA在疾病中的贡献知之甚少。目前已报道的慢性肾病与LncRNA的文章80%都是有关DN。不到10项研究报道了不同类型的慢性肾脏疾病与LncRNA之间的发现结果。

首先是局灶性节段性肾小球硬化(focal segmental glomerulosclerosis, FSGS)。FSGS是导致大量蛋白尿的一个常见病因, 多发于儿童和青少年, 也是成年人发展为慢性肾衰竭的重要原因。有研究发现LncRNA LOC105375913在5个FSGS患者的肾小管细胞中显著增加, 并且在体外培养人肾小管上皮细胞HK2中发现, 这种上调是由C3a/p38/XBP-1s信号通路诱导的。LOC105375913通过结合miR-27b并持续地过表达Snail发挥其促纤维化功能^[46]。

针对有关FSGS中的LncRNA与肾小球变化的关系, Hu等^[47]研究发现了LOC105374325在FSGS患者的足细胞中上调并诱导足细胞凋亡。同样, 这种LncRNA的作用也是通过p38和C/EPBβ通路以及作为miR-34c和miR-196a/b的“海绵”发挥作用, 这2个miRNA通常调节促凋亡蛋白的表达。

4.3 膜性肾病

膜性肾病(membranous nephropathy, MN)属于肾小球肾炎, 肾小球毛细血管袢上皮侧有大量免疫复合物沉积; 临床表现为肾病综合征。LncRNA与MN的研究还处于起步阶段, 相关的研究相对较少。Huang等^{[48, 49]}在小鼠MN模型中发现了第一组失调的LncRNA, Xist和NEAT1。作为已知的最长的LncRNA XIST, 其在X染色体失活中的作用与MN相关。在疾病状态下, 它们在肾小管上皮细胞和肾小球细胞中都显著上调。在体外, 使用脂多糖诱导足细胞损伤后, Xist稳定升高, 但NEAT1未升高。Xist可以在尿液中有效地检测到, 并且与膜性肾病的严重程度有很强的相关性。进一步研究发现, Xist的调控可能受到翻译后修饰的控制。在小鼠膜性肾病模型中H3K27me3水平显著下调, 染色体免疫沉淀实验也发现Xist启动子区域的H3K27me3下调, 表明H3K27me3在Xist启动子区域的减少导致尿Xist水平升高; 细胞培养中的数据表明, Xist通过隔离miR-217和持续上调TLR4对足细胞发挥促凋亡作用。这表明Xist有望被用作检测MN的生物标志物。以上研究表明, 通过LncRNA的表观遗传失调导致的基因表达的改变正日益被认为是疾病发生发展的重要因素。

4.4 狼疮性肾炎

狼疮性肾炎(lupus nephritis, LN)是我国最常见的继发性肾小球疾病, 是机体产生内源性抗体所诱导的免疫复合物疾病。红斑狼疮患者的B细胞高度活跃增殖, 产生多种自身抗体, 这些抗原抗体形成的免疫复合物沉积在全身各个组织, 尤其在肾小球, 并激活补体通路。最近的研究中, Liao等^[50]在LN患者的肾活检中发现了一些LncRNA的差异表达。与健康对照组相比, 发现LncRNA RP11-2B6.2在LN患者的肾组织中上调。使用HELA和HK-2细胞系研究发现, RP11-2B6.2的过表达抑制了细胞因子信号传导抑制蛋白1 (suppressor of cytokine signaling 1, SOCS1), SOCS1是已知的1型干扰素(interferon type 1, IFN-1)信号传导途径的调节因子, 因此RP11-2B6.2增强了IFN-1信号传导途径。通过进一步研究发现, RP11-2B6.2的下调与SOCS1启动子区域中的染色质开放状态一致。基于这一发现, Liao等提出SOCS1的抑制作用是通过一种未确定的表观遗传学机制来实现的。Wu等^[51]从系统性红斑狼疮患者、类风湿性关节炎患者和正常人的外周血的单核细胞提取LncRNA, 发现红斑狼疮患者体内linc0949和linc0597的表达与其他两组相比显著下调, 其中狼疮性肾炎患者的linc0949显著下调, 且在狼疮性肾炎活动期下调更为明显, 提示linc0949可能与狼疮性肾炎的发生发展有关。linc0949和linc0597参与调节了疾病中的一些促炎因子(如白介素-6、肿瘤坏死因子-α等), 促进了疾病的进展, 但具体机制尚不明确, 或许可成为潜在的标志物, 为治疗狼疮性肾炎提供新的选择。

4.5 IgA肾病

IgA肾病是一种常见的原发性肾小球疾病, IgA肾脏疾病病理类型多样化, 可表现为肾小球系膜细胞增生, 基质增多, 伴有IgA广泛地沉积在肾小球系膜区。Zuo等^[52]收集了正常人和IgA肾病患者的外周血做基因芯片分析, 找到了167个差异表达的LncRNA和94个差异表达的mRNA, 分析了这些LncRNA潜在的生物学功能和机制, 但具体的功能尚不明确。但这些发现为进一步研究IgA肾病中的LncRNA奠定了基础, 有可能成为潜在的生物标志物和治疗的新靶点。

以上总结了已经报道的相关慢性肾病的LncRNA, 并分析了这些LncRNA在疾病发生发展过程中的分子机制和功能(表 1)^{[20-42, 46-51]}。然而, 除了在糖尿病肾病中对这些LncRNA研究的较为深入, 对于其他类型的慢性肾病相关的LncRNA大多为描述性的研究, 因此未来的工作将需要填补这一空白。

5 总结与展望

收起

目前, 随着对LncRNA的进一步研究, 人们重新认识了中心法则, 丰富了分子生物学和遗传学的内容。尽管研究者已经初步了解LncRNA的调控机制以及它们与肾脏的关系, 但是在肾脏发育和肾脏疾病发生发展过程中, LncRNA所介导的基因表达调控网络及其作用机制还有待进一步探索; 此外, LncRNA所含的信息量非常丰富, 参与表达调控的分子机制多种多样, 决定了LncRNA与肾脏的研究潜力巨大。因此, LncRNA将有可能成为肾脏发育与肾脏疾病发病机制研究中的热点。随着新一代测序技术及生物信息学的迅猛发展, 研究者将更加高效地发现与肾脏相关的LncRNA, 并进一步探讨其影响肾脏疾病的发生和发展机制, 为肾脏疾病提供新的诊断依据和潜在的治疗靶点。科学研究最终可以利用靶向组织特异性的特点, 将LncRNA作为糖尿病肾病等肾脏疾病特异治疗新靶点, 实现精准医疗。

基金

收起

十三五“重大新药创制”科技重大专项(2018ZX09711001)

参考文献

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2019年第54卷第11期

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doi: 10.16438/j.0513-4870.2019-0464

接收时间：2019-06-12
首发时间：2026-01-26
出版时间：2019-11-12

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收稿日期：2019-06-12
修回日期：2019-08-08

基金

十三五“重大新药创制”科技重大专项(2018ZX09711001)

作者信息

中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

*张森, Tel: 86-10-63165207, E-mail: zhangs@imm.ac.cn; chxg@imm.ac.cn

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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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	LncRNA	Description	Suggested function	Reference
Diabetic nephropathy	TUG1	Recruits PGC-1α to promoter and serves as a sponge for miR-377	miRNA binding/protein binding/transcriptional activation	[20, 27]
NEAT1	Activates the AKT/mTOR signal and serves as a sponge for miR-27b-3p	miRNA binding/expression changed	[21, 32]
MALAT1	Associated with podocyte damage and involve in inflammatory processes	miRNA binding/expression changed	[22, 25, 26]
PVT1	Serves as a host of miRNA 1207-5p and regulates ECM formation	Expression changed	[23, 28-31]
Lnc-MGC	Harbors 40 miRNAs and regulated by endoplasmic reticulum stress signal	miRNA binding	[24]
CYPB1-PS1-001	Downregulated in early phases of DN	Protein binding	[33, 34]
LINC01619	Induces oxidative podocyte damage by serving as a sponge for miR-27a	miRNA binding	[35]
Gm6135	Impair miR-203-3p and downregulate of TLR4	miRNA binding	[36]
1700020I14Rik	Reduces cellular proliferation via inhibition of miR-34-a-5p	miRNA binding	[37]
150Rik	Promotes proliferation by sponging miR-451	miRNA binding	[38]
H19	Induces miR-675 and modulates vitamin D receptor expression	Transcriptional activation	[39]
ERBB4-IR	Suppresses miR-29b and serves as target gene of smad3	Transcriptional repression	[40, 41]
ZEB1-AS1	Enhances ZEB1 by promoting H3K4me3 histone modification	Recruitment of histone modifications	[42]
Focal segmental glomerulosclerosis	LOC105375913	Increases in tubular cells and induced by the C3a/p38/XBP-1s pathway	miRNA binding	[46]
LOC105374325	Serves as a sponge for miR-34c and miR-196a/b	miRNA binding	[47]
Membranous nephropathy	Xist, NEAT1	Sequestrate miR-217 and upregulate of TLR4	miRNA binding	[48, 49]
Lupus nephritis	RP11-2B6.2	Inhibits SOCS1and increases the IFN-1 signaling pathway	Epigenetic inhibition	[50]
LINC0949, LINC0597	Participate in the synthesis of pro-inflammatory factors	Unknown	[51]

LncRNA

Description

Suggested function

Reference

Diabetic nephropathy

TUG1

Recruits PGC-1α to promoter and serves as a sponge for miR-377

miRNA binding/protein binding/transcriptional activation

[20, 27]

NEAT1

Activates the AKT/mTOR signal and serves as a sponge for miR-27b-3p

miRNA binding/expression changed