糖尿病肾病与细胞因子的相关性研究进展

刘雪峰　张睿



糖尿病肾病与细胞因子的相关性研究进展

刘雪峰张睿

糖尿病肾病(DN)为糖尿病常见并发症之一，其病因大致分为遗传因素、糖脂代谢紊乱、细胞因子、炎性反应、微循环障碍等，多种病因可单独或协同对肾小球、肾血管、肾小管、肾间质产生损害，最终导致肾衰竭，细胞因子激活是其病变形成的直接原因，细胞因子间相互作用形成了糖尿病肾病细胞因子网络，主要包括肿瘤坏死因子(TNF-α)、转化生长因子(TGF-β)、白介素因子(IL-18、IL-6、IL-8)、胰岛素样生长因子-1(IGF-1)、单核细胞趋化蛋白-1(MCP-1)、结缔组织生长因子(CTGF)、血管内皮生长因子(VEGF)、血小板衍生因子(PDGF-BB)等。对DN与细胞因子的相关性研究为DN治疗提供了理论基础支持，对DN做出早期诊断和治疗提供了参考。

细胞因子；糖尿病肾病

糖尿病肾病(DN)是糖尿病最严重的并发症之一，是导致1型糖尿病患者死亡的主要原因，而在2型糖尿病中危险程度仅次于心脑的并发症[1]。流行病学显示1型糖尿病患糖尿病肾病的几率为33%～40%，2型糖尿病患糖尿病肾病的几率为20%左右[2]。1型和2型的糖尿病患者一旦出现蛋白尿，5年以后发生肾衰的患者超过50%，10年以后发生肾衰的患者超过80%[3]。Sun等[4]研究发现DN患者肾脏中有巨噬细胞的浸润之后，后续研究表明内皮因子-1(ET-1)、肿瘤坏死因子(TNF-α)、白介素-6(IL-6)等因子可以加重糖尿病患者的肾脏损害，加速糖尿病肾病的进程，逐渐证实了炎性因子介导DN的发生发展。炎性因子、生长因子与趋化因子等众多细胞因子通过各自的旁分泌、自分泌发挥功能，之间又具有协同与拮抗的作用。细胞因子是由免疫细胞和非免疫细胞经刺激而合成的一类具有生物学活性的小分子蛋白质，包括炎性细胞因子、趋化因子、生长因子等，在DN的发生发展过程中扮演重要角色[5]。现将近年来学者对细胞因子造成DN肾脏组织损害机制的研究和进展综述如下。

1　炎性细胞因子

炎性细胞因子是参与各种炎性反应的细胞因子，起主要作用的因子有肿瘤坏死因子(TNF-α)、转化生长因子(TGF-β)、白介素因子(IL-18、IL-6、IL-8)等。

1.1TNF-αTNF-α为多功能细胞因子，其联合高糖可损坏肾脏系膜细胞，通过扰乱血管扩张神经及血管收缩神经的平衡，导致肾脏血流动力学异常，最严重的是TNF-α可增加胰岛素抵抗，使血糖维持高值，增加并发症的发生几率及进展速度[6,7]。TNF-α可使胰岛素受体底物磷酸化受到抑制，并使外周组织对葡萄糖摄取减少，导致胰岛素抵抗，脂肪分解受到刺激，从而胰岛素受体底物激活，葡萄糖转运易位干扰[8,9]。TNF-α可引起肾小球上皮细胞和系膜细胞毒性，可能引起肾损害[10,11]。TNF-α随着DN的病情进展而升高，且TNF-α水平升高显示发生DN的几率增大[12]，其可能机制为：与肾小管基膜增厚有关；与足细胞数量减少和损伤有关；促进系膜细胞酶原激活物抑制剂1、纤维连接蛋白的表达，使外基质形成，并抑制其降解[13,14]。

1.2IL-8IL-8可促使血管活性因子产生，引起血管收缩，导致血管内皮损伤，血管通透性改变，产生蛋白尿，又可诱导其他炎性因子的产生及氧化反应的发生，共同加速DN的进展[15,16]。高血糖的环境又可促使IL-8的分泌增加，即使在DN早期也可发现IL-8的存在, IL-8水平升高与HbA1c有关，且与糖尿病肾损害有一定关系[17]。

1.3IL-6IL-6可通过促进T、B细胞过度激活和增殖,加速细胞凋亡,促进胰岛B细胞破坏,加重病情，又可促进肾脏系膜增殖，产生蛋白尿[18,19]。IL-6刺激系膜细胞，氧自由基生成，过氧化脂质代谢产物增加,细胞内膜和基膜损伤,产生蛋白尿,致使DN发生[20,21]。

1.4IL-18IL-18促进肾小球系膜细胞有丝分裂、增殖，产生、释放细胞因子，加重炎性细胞在肾小球内积聚，加速DN的进程[22,23]。IL-18可使细胞外基质蛋白分子合成增加,抑制基质蛋白分子降解,引起肾小球纤维化或硬化[24]； IL-18促进体内其他炎性因子聚集和合成，加剧肾小球损伤[25]。

1.5IL-17α有研究发现IL-17α可介导产生胰岛素，加重糖尿病病情，还与肾间质、肾小管的病变有关[26]。

2　生长因子、趋化因子

2.1转化生长因子(TGF)TGF-β可促使肾小球肥大，刺激细胞外基质合成，肾小球细胞外基质合成增加，因介导足细胞损伤致肾小球硬化，导致蛋白尿形成[27]。TGF-β的过度产生还可促进肾小管上皮-肌成纤维细胞转分化引起肾间质纤维化，加速DN的进程[28]。TGF-β1可刺激细胞外基质的大量分泌， 同时抑制基质蛋白降解酶,促使肾组织硬化,加重DN。TGF-β1可直接诱导肾脏间质纤维化；可诱导足细胞凋亡[29]。

2.2胰岛素样生长因子-1(IGF-1)IGF-1是肾脏正常生长发育所需的一种重要生长因子，具有促进细胞增生、扩张微血管、促进细胞外基质生成的作用，导致肾小球肥大、肾间质化[30]。IGF-1在DN发生发展中主要作用机制为：促进肾脏系膜细胞外基质增多和细胞增生[31]；刺激纤维链接蛋白、Ⅳ型胶原蛋白、层黏蛋白等细胞外基层蛋白合成[32]；增加系膜细胞对葡萄糖摄取[33]；IGF-1聚集与肾小球肥大有关， 同时IGF-1刺激肾小球系膜细胞增生也可致肾小球肥大，IGF-1通过诱导肾脏缓激肽表达，促进NO产生[34]。另研究表明IGF-1可以损害足细胞，产生尿蛋白[35]。

2.3血管内皮生长因子(VEGF)VEGF是一种高度特异性血管内皮细胞生长因子,实验研究表明VEGF可在糖尿病大鼠肾脏发生病变时在肾小球内的表达上调，增加肾脏新血管产生，参与糖尿病肾病早期病变，VEGF又称为血管通透因子，使肾小球血管通透性增加，处于高滤过状态，加重糖尿病肾病蛋白尿的症状[36]。VEGF参与DN主要发病机制：促进上皮细胞和成纤维细胞增生，使肾小管细胞和肾小球肥大；促进肾小球基膜纤维化和增厚；刺激血管内皮细胞增殖、分化， 增加血管内皮细胞通透性，导致大量血浆蛋白渗出，促进蛋白尿产生； 促进胶原生成，致细胞外基质增厚[37-39]。

2.4结缔组织生长因子(CTGF)CTGF主要通过增加细胞外基质及纤维原细胞，加速肾间质纤维化[40]；作为TGF-β的下游因子，还可介导 TGF-β1促使肾小球细胞肥大、肾小管上皮细胞向肌成纤维细胞转分化，加速肾脏损伤[41]。CTGF在DN中主要作用机制：与肾小管基膜增厚有关；与足细胞数量减少和损伤有关；通过上调系膜细胞纤维连接蛋白表达，促进系膜细胞外基质形成，并抑制其降解[42,43]。

2.5血小板衍生因子(PDGF-BB)PDGF-BB在肾脏中的作用主要包括诱导肾小球系膜细胞增生，使肾小球肥大，促进细胞外基质积聚使基底膜增生，进而使肾小球基底膜的增厚，肾小球硬化，通透性增加，产生蛋白尿[44]。研究表明PDGF-BB还可诱导TGF-β及其受体的合成增多,使细胞外基质合成增加，加速肾小球细胞增生、肥大[45]。

2.6单核细胞趋化蛋白-1(MCP-1)MCP-1主要参与单核细胞及巨噬细胞的活化和浸润，作为糖尿病肾病最重要的生物学标志物，通过趋化巨噬细胞浸润肾小球及肾小管间质，引起糖尿病肾血管损伤及肾基质纤维化，以及与体内氧化应激状态相结合共同损伤肾组织[46]。MCP-1在DN患者中作用机制：高血糖刺激蛋白含量增高及MCP-1 mRNA高表达；DN患者PDGF等细胞因子水平升高，MCP-1在肾内皮细胞、系膜细胞的高表达； DN患者存在血脂代谢紊乱，使低密度脂蛋白升高，刺激系膜细胞MCP-1 mRNA表达增高[47,48]。

2.7肝细胞生长因子(HGF)HGF作为一种抗纤维化、诱导和调节的因子，可对肾脏起保护作用， 防止肾纤维化。HGF与中期因子是一对抗损伤与损伤因子， DN早期HGF分泌增加， 抑制TGF-β产生，但随中期因子增多，TGF-β占优势，抑制HGF产生，抗纤维化作用减弱，导致DN发展[49]。HGF是一种强烈的有丝分裂原而作用于成熟肝细胞， 有促细胞迁移、 形态发生、有丝分裂等作用。早期高血糖时， 细胞损伤引发机体发生防御反应， 使 HGF/c-met上调，促进细胞有丝分裂， 修复损伤细 胞；持续的高血糖，使细胞防御能力下降，逐渐降低HGF/c-met表达，转化TGF-β、CTGF增多，使ECM蛋白表达增多， 抑制降解， 致细胞肥大，最终引起肾纤维化[50]。

3　其他

3.1内皮素(ET)ET有ET-1、ET-2、ET-3三种异构肽，由内皮细胞合成分泌。ET-1有强而持久的缩血管作用，并可促进平滑肌增值作用。ET-1致DN的主要机制为：与TNF-α、PDGF-BB等因子对肾脏损害相关；诱导TGF-β、血管紧张素转换酶产生，使系膜增生、肾肥大管收缩及细胞外基质堆积；抑制肾脏对水重吸收，使肾小球动脉硬化，肾系膜增生，肾小球滤过率下降[51]。肾组织ET升高又通过多种机制加速DN的发展，形成恶性循环[52]。

3.2核因子κB(NF-κB)NF-κB是一种核转录因子，调控细胞增殖分化、炎症和免疫等过程，DN早期存在核因子B信号转导途径的激活和持续高表达，NF-κB可促进肾组织巨噬、单核细胞浸润，使组织纤维化及炎症，从而损伤肾间质[53]。糖基化终末产物是DN的重要相关因子，其与相应受体结合后能激活NF-κB，致细胞间黏附分子1 释放，从而参与DN发生、发展[54]。

DN是糖尿病主要并发症之一，其发病机制复杂，细胞因子网络调控在DN发生发展过程中起重要作用。细胞因子间相互影响，相互协调。在血流动力学变化、晚期糖基化终末产物和高血糖等作用下，多种细胞因子分泌增加，细胞因子部分被激活，被激活的细胞因子又激活或抑制其他细胞因子，促进成纤维细胞增殖，和ECM堆积，ET-1可收缩球后毛细血管床而影响球后微循环，引起肾小管上皮细胞缺血，加重肾脏损害。如ET-1可诱导TGF-β产生，TGF-β诱导和激活VEGF又抑制了NF-κB的活性，并使血清HGF水平降低。TGF-β功能多样， 在细胞因子网络中起到了重要作用， 故被称为细胞因子网络的核心因子， 与其他各种细胞因子共同促进D N的发生、发展。

随着细胞因子研究的不断深入，为诊断和治疗DN提供了新的方法和新靶点。如GTGF可为预防肾小球纤维化的重要指标，血清IL-18水平可作为诊断DN的重要手段，而抗内皮素受体 A阻断剂、TGF-β抗体等可作为潜在治疗DN药物。HGF等细胞因子也有可能为治疗DN临床研究的新思路。细胞因子在DN发病机制中具有重要作用，细胞因子网络的相关研究为DN的预防和个体化药物治疗开辟了新途径，有利于阻止或延缓DN发生、发展，提高DN患者的生活质量。

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10.3969/j.issn.1002-7386.2016.21.038·综述与讲座·

项目来源：国家自然科学基金项目(编号：81400812)

054001河北省邢台市第一医院药剂科(刘雪峰)；河北医科大学第一医院科研中心(张睿)

R 587.24

A

1002-7386(2016)21-3323-04

2016-04-12)