劉雪峰　張睿

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糖尿病腎病與細(xì)胞因子的相關(guān)性研究進(jìn)展

劉雪峰張睿

糖尿病腎病(DN)為糖尿病常見(jiàn)并發(fā)癥之一，其病因大致分為遺傳因素、糖脂代謝紊亂、細(xì)胞因子、炎性反應(yīng)、微循環(huán)障礙等，多種病因可單獨(dú)或協(xié)同對(duì)腎小球、腎血管、腎小管、腎間質(zhì)產(chǎn)生損害，最終導(dǎo)致腎衰竭，細(xì)胞因子激活是其病變形成的直接原因，細(xì)胞因子間相互作用形成了糖尿病腎病細(xì)胞因子網(wǎng)絡(luò)，主要包括腫瘤壞死因子(TNF-α)、轉(zhuǎn)化生長(zhǎng)因子(TGF-β)、白介素因子(IL-18、IL-6、IL-8)、胰島素樣生長(zhǎng)因子-1(IGF-1)、單核細(xì)胞趨化蛋白-1(MCP-1)、結(jié)締組織生長(zhǎng)因子(CTGF)、血管內(nèi)皮生長(zhǎng)因子(VEGF)、血小板衍生因子(PDGF-BB)等。對(duì)DN與細(xì)胞因子的相關(guān)性研究為DN治療提供了理論基礎(chǔ)支持，對(duì)DN做出早期診斷和治療提供了參考。

細(xì)胞因子；糖尿病腎病

糖尿病腎病(DN)是糖尿病最嚴(yán)重的并發(fā)癥之一，是導(dǎo)致1型糖尿病患者死亡的主要原因，而在2型糖尿病中危險(xiǎn)程度僅次于心腦的并發(fā)癥[1]。流行病學(xué)顯示1型糖尿病患糖尿病腎病的幾率為33%～40%，2型糖尿病患糖尿病腎病的幾率為20%左右[2]。1型和2型的糖尿病患者一旦出現(xiàn)蛋白尿，5年以后發(fā)生腎衰的患者超過(guò)50%，10年以后發(fā)生腎衰的患者超過(guò)80%[3]。Sun等[4]研究發(fā)現(xiàn)DN患者腎臟中有巨噬細(xì)胞的浸潤(rùn)之后，后續(xù)研究表明內(nèi)皮因子-1(ET-1)、腫瘤壞死因子(TNF-α)、白介素-6(IL-6)等因子可以加重糖尿病患者的腎臟損害，加速糖尿病腎病的進(jìn)程，逐漸證實(shí)了炎性因子介導(dǎo)DN的發(fā)生發(fā)展。炎性因子、生長(zhǎng)因子與趨化因子等眾多細(xì)胞因子通過(guò)各自的旁分泌、自分泌發(fā)揮功能，之間又具有協(xié)同與拮抗的作用。細(xì)胞因子是由免疫細(xì)胞和非免疫細(xì)胞經(jīng)刺激而合成的一類具有生物學(xué)活性的小分子蛋白質(zhì)，包括炎性細(xì)胞因子、趨化因子、生長(zhǎng)因子等，在DN的發(fā)生發(fā)展過(guò)程中扮演重要角色[5]?，F(xiàn)將近年來(lái)學(xué)者對(duì)細(xì)胞因子造成DN腎臟組織損害機(jī)制的研究和進(jìn)展綜述如下。

1　炎性細(xì)胞因子

炎性細(xì)胞因子是參與各種炎性反應(yīng)的細(xì)胞因子，起主要作用的因子有腫瘤壞死因子(TNF-α)、轉(zhuǎn)化生長(zhǎng)因子(TGF-β)、白介素因子(IL-18、IL-6、IL-8)等。

1.1TNF-αTNF-α為多功能細(xì)胞因子，其聯(lián)合高糖可損壞腎臟系膜細(xì)胞，通過(guò)擾亂血管擴(kuò)張神經(jīng)及血管收縮神經(jīng)的平衡，導(dǎo)致腎臟血流動(dòng)力學(xué)異常，最嚴(yán)重的是TNF-α可增加胰島素抵抗，使血糖維持高值，增加并發(fā)癥的發(fā)生幾率及進(jìn)展速度[6,7]。TNF-α可使胰島素受體底物磷酸化受到抑制，并使外周組織對(duì)葡萄糖攝取減少，導(dǎo)致胰島素抵抗，脂肪分解受到刺激，從而胰島素受體底物激活，葡萄糖轉(zhuǎn)運(yùn)易位干擾[8,9]。TNF-α可引起腎小球上皮細(xì)胞和系膜細(xì)胞毒性，可能引起腎損害[10,11]。TNF-α隨著DN的病情進(jìn)展而升高，且TNF-α水平升高顯示發(fā)生DN的幾率增大[12]，其可能機(jī)制為：與腎小管基膜增厚有關(guān)；與足細(xì)胞數(shù)量減少和損傷有關(guān)；促進(jìn)系膜細(xì)胞酶原激活物抑制劑1、纖維連接蛋白的表達(dá)，使外基質(zhì)形成，并抑制其降解[13,14]。

1.2IL-8IL-8可促使血管活性因子產(chǎn)生，引起血管收縮，導(dǎo)致血管內(nèi)皮損傷，血管通透性改變，產(chǎn)生蛋白尿，又可誘導(dǎo)其他炎性因子的產(chǎn)生及氧化反應(yīng)的發(fā)生，共同加速DN的進(jìn)展[15,16]。高血糖的環(huán)境又可促使IL-8的分泌增加，即使在DN早期也可發(fā)現(xiàn)IL-8的存在, IL-8水平升高與HbA1c有關(guān)，且與糖尿病腎損害有一定關(guān)系[17]。

1.3IL-6IL-6可通過(guò)促進(jìn)T、B細(xì)胞過(guò)度激活和增殖,加速細(xì)胞凋亡,促進(jìn)胰島B細(xì)胞破壞,加重病情，又可促進(jìn)腎臟系膜增殖，產(chǎn)生蛋白尿[18,19]。IL-6刺激系膜細(xì)胞，氧自由基生成，過(guò)氧化脂質(zhì)代謝產(chǎn)物增加,細(xì)胞內(nèi)膜和基膜損傷,產(chǎn)生蛋白尿,致使DN發(fā)生[20,21]。

1.4IL-18IL-18促進(jìn)腎小球系膜細(xì)胞有絲分裂、增殖，產(chǎn)生、釋放細(xì)胞因子，加重炎性細(xì)胞在腎小球內(nèi)積聚，加速DN的進(jìn)程[22,23]。IL-18可使細(xì)胞外基質(zhì)蛋白分子合成增加,抑制基質(zhì)蛋白分子降解,引起腎小球纖維化或硬化[24]； IL-18促進(jìn)體內(nèi)其他炎性因子聚集和合成，加劇腎小球損傷[25]。

1.5IL-17α有研究發(fā)現(xiàn)IL-17α可介導(dǎo)產(chǎn)生胰島素，加重糖尿病病情，還與腎間質(zhì)、腎小管的病變有關(guān)[26]。

2　生長(zhǎng)因子、趨化因子

2.1轉(zhuǎn)化生長(zhǎng)因子(TGF)TGF-β可促使腎小球肥大，刺激細(xì)胞外基質(zhì)合成，腎小球細(xì)胞外基質(zhì)合成增加，因介導(dǎo)足細(xì)胞損傷致腎小球硬化，導(dǎo)致蛋白尿形成[27]。TGF-β的過(guò)度產(chǎn)生還可促進(jìn)腎小管上皮-肌成纖維細(xì)胞轉(zhuǎn)分化引起腎間質(zhì)纖維化，加速DN的進(jìn)程[28]。TGF-β1可刺激細(xì)胞外基質(zhì)的大量分泌， 同時(shí)抑制基質(zhì)蛋白降解酶,促使腎組織硬化,加重DN。TGF-β1可直接誘導(dǎo)腎臟間質(zhì)纖維化；可誘導(dǎo)足細(xì)胞凋亡[29]。

2.2胰島素樣生長(zhǎng)因子-1(IGF-1)IGF-1是腎臟正常生長(zhǎng)發(fā)育所需的一種重要生長(zhǎng)因子，具有促進(jìn)細(xì)胞增生、擴(kuò)張微血管、促進(jìn)細(xì)胞外基質(zhì)生成的作用，導(dǎo)致腎小球肥大、腎間質(zhì)化[30]。IGF-1在DN發(fā)生發(fā)展中主要作用機(jī)制為：促進(jìn)腎臟系膜細(xì)胞外基質(zhì)增多和細(xì)胞增生[31]；刺激纖維鏈接蛋白、Ⅳ型膠原蛋白、層黏蛋白等細(xì)胞外基層蛋白合成[32]；增加系膜細(xì)胞對(duì)葡萄糖攝取[33]；IGF-1聚集與腎小球肥大有關(guān)， 同時(shí)IGF-1刺激腎小球系膜細(xì)胞增生也可致腎小球肥大，IGF-1通過(guò)誘導(dǎo)腎臟緩激肽表達(dá)，促進(jìn)NO產(chǎn)生[34]。另研究表明IGF-1可以損害足細(xì)胞，產(chǎn)生尿蛋白[35]。

2.3血管內(nèi)皮生長(zhǎng)因子(VEGF)VEGF是一種高度特異性血管內(nèi)皮細(xì)胞生長(zhǎng)因子,實(shí)驗(yàn)研究表明VEGF可在糖尿病大鼠腎臟發(fā)生病變時(shí)在腎小球內(nèi)的表達(dá)上調(diào)，增加腎臟新血管產(chǎn)生，參與糖尿病腎病早期病變，VEGF又稱為血管通透因子，使腎小球血管通透性增加，處于高濾過(guò)狀態(tài)，加重糖尿病腎病蛋白尿的癥狀[36]。VEGF參與DN主要發(fā)病機(jī)制：促進(jìn)上皮細(xì)胞和成纖維細(xì)胞增生，使腎小管細(xì)胞和腎小球肥大；促進(jìn)腎小球基膜纖維化和增厚；刺激血管內(nèi)皮細(xì)胞增殖、分化， 增加血管內(nèi)皮細(xì)胞通透性，導(dǎo)致大量血漿蛋白滲出，促進(jìn)蛋白尿產(chǎn)生； 促進(jìn)膠原生成，致細(xì)胞外基質(zhì)增厚[37-39]。

2.4結(jié)締組織生長(zhǎng)因子(CTGF)CTGF主要通過(guò)增加細(xì)胞外基質(zhì)及纖維原細(xì)胞，加速腎間質(zhì)纖維化[40]；作為T(mén)GF-β的下游因子，還可介導(dǎo) TGF-β1促使腎小球細(xì)胞肥大、腎小管上皮細(xì)胞向肌成纖維細(xì)胞轉(zhuǎn)分化，加速腎臟損傷[41]。CTGF在DN中主要作用機(jī)制：與腎小管基膜增厚有關(guān)；與足細(xì)胞數(shù)量減少和損傷有關(guān)；通過(guò)上調(diào)系膜細(xì)胞纖維連接蛋白表達(dá)，促進(jìn)系膜細(xì)胞外基質(zhì)形成，并抑制其降解[42,43]。

2.5血小板衍生因子(PDGF-BB)PDGF-BB在腎臟中的作用主要包括誘導(dǎo)腎小球系膜細(xì)胞增生，使腎小球肥大，促進(jìn)細(xì)胞外基質(zhì)積聚使基底膜增生，進(jìn)而使腎小球基底膜的增厚，腎小球硬化，通透性增加，產(chǎn)生蛋白尿[44]。研究表明PDGF-BB還可誘導(dǎo)TGF-β及其受體的合成增多,使細(xì)胞外基質(zhì)合成增加，加速腎小球細(xì)胞增生、肥大[45]。

2.6單核細(xì)胞趨化蛋白-1(MCP-1)MCP-1主要參與單核細(xì)胞及巨噬細(xì)胞的活化和浸潤(rùn)，作為糖尿病腎病最重要的生物學(xué)標(biāo)志物，通過(guò)趨化巨噬細(xì)胞浸潤(rùn)腎小球及腎小管間質(zhì)，引起糖尿病腎血管損傷及腎基質(zhì)纖維化，以及與體內(nèi)氧化應(yīng)激狀態(tài)相結(jié)合共同損傷腎組織[46]。MCP-1在DN患者中作用機(jī)制：高血糖刺激蛋白含量增高及MCP-1 mRNA高表達(dá)；DN患者PDGF等細(xì)胞因子水平升高，MCP-1在腎內(nèi)皮細(xì)胞、系膜細(xì)胞的高表達(dá)； DN患者存在血脂代謝紊亂，使低密度脂蛋白升高，刺激系膜細(xì)胞MCP-1 mRNA表達(dá)增高[47,48]。

2.7肝細(xì)胞生長(zhǎng)因子(HGF)HGF作為一種抗纖維化、誘導(dǎo)和調(diào)節(jié)的因子，可對(duì)腎臟起保護(hù)作用， 防止腎纖維化。HGF與中期因子是一對(duì)抗損傷與損傷因子， DN早期HGF分泌增加， 抑制TGF-β產(chǎn)生，但隨中期因子增多，TGF-β占優(yōu)勢(shì)，抑制HGF產(chǎn)生，抗纖維化作用減弱，導(dǎo)致DN發(fā)展[49]。HGF是一種強(qiáng)烈的有絲分裂原而作用于成熟肝細(xì)胞， 有促細(xì)胞遷移、 形態(tài)發(fā)生、有絲分裂等作用。早期高血糖時(shí)， 細(xì)胞損傷引發(fā)機(jī)體發(fā)生防御反應(yīng)， 使 HGF/c-met上調(diào)，促進(jìn)細(xì)胞有絲分裂， 修復(fù)損傷細(xì) 胞；持續(xù)的高血糖，使細(xì)胞防御能力下降，逐漸降低HGF/c-met表達(dá)，轉(zhuǎn)化TGF-β、CTGF增多，使ECM蛋白表達(dá)增多， 抑制降解， 致細(xì)胞肥大，最終引起腎纖維化[50]。

3　其他

3.1內(nèi)皮素(ET)ET有ET-1、ET-2、ET-3三種異構(gòu)肽，由內(nèi)皮細(xì)胞合成分泌。ET-1有強(qiáng)而持久的縮血管作用，并可促進(jìn)平滑肌增值作用。ET-1致DN的主要機(jī)制為：與TNF-α、PDGF-BB等因子對(duì)腎臟損害相關(guān)；誘導(dǎo)TGF-β、血管緊張素轉(zhuǎn)換酶產(chǎn)生，使系膜增生、腎肥大管收縮及細(xì)胞外基質(zhì)堆積；抑制腎臟對(duì)水重吸收，使腎小球動(dòng)脈硬化，腎系膜增生，腎小球?yàn)V過(guò)率下降[51]。腎組織ET升高又通過(guò)多種機(jī)制加速DN的發(fā)展，形成惡性循環(huán)[52]。

3.2核因子κB(NF-κB)NF-κB是一種核轉(zhuǎn)錄因子，調(diào)控細(xì)胞增殖分化、炎癥和免疫等過(guò)程，DN早期存在核因子B信號(hào)轉(zhuǎn)導(dǎo)途徑的激活和持續(xù)高表達(dá)，NF-κB可促進(jìn)腎組織巨噬、單核細(xì)胞浸潤(rùn)，使組織纖維化及炎癥，從而損傷腎間質(zhì)[53]。糖基化終末產(chǎn)物是DN的重要相關(guān)因子，其與相應(yīng)受體結(jié)合后能激活NF-κB，致細(xì)胞間黏附分子1 釋放，從而參與DN發(fā)生、發(fā)展[54]。

DN是糖尿病主要并發(fā)癥之一，其發(fā)病機(jī)制復(fù)雜，細(xì)胞因子網(wǎng)絡(luò)調(diào)控在DN發(fā)生發(fā)展過(guò)程中起重要作用。細(xì)胞因子間相互影響，相互協(xié)調(diào)。在血流動(dòng)力學(xué)變化、晚期糖基化終末產(chǎn)物和高血糖等作用下，多種細(xì)胞因子分泌增加，細(xì)胞因子部分被激活，被激活的細(xì)胞因子又激活或抑制其他細(xì)胞因子，促進(jìn)成纖維細(xì)胞增殖，和ECM堆積，ET-1可收縮球后毛細(xì)血管床而影響球后微循環(huán)，引起腎小管上皮細(xì)胞缺血，加重腎臟損害。如ET-1可誘導(dǎo)TGF-β產(chǎn)生，TGF-β誘導(dǎo)和激活VEGF又抑制了NF-κB的活性，并使血清HGF水平降低。TGF-β功能多樣， 在細(xì)胞因子網(wǎng)絡(luò)中起到了重要作用， 故被稱為細(xì)胞因子網(wǎng)絡(luò)的核心因子， 與其他各種細(xì)胞因子共同促進(jìn)D N的發(fā)生、發(fā)展。

隨著細(xì)胞因子研究的不斷深入，為診斷和治療DN提供了新的方法和新靶點(diǎn)。如GTGF可為預(yù)防腎小球纖維化的重要指標(biāo)，血清IL-18水平可作為診斷DN的重要手段，而抗內(nèi)皮素受體 A阻斷劑、TGF-β抗體等可作為潛在治療DN藥物。HGF等細(xì)胞因子也有可能為治療DN臨床研究的新思路。細(xì)胞因子在DN發(fā)病機(jī)制中具有重要作用，細(xì)胞因子網(wǎng)絡(luò)的相關(guān)研究為DN的預(yù)防和個(gè)體化藥物治療開(kāi)辟了新途徑，有利于阻止或延緩DN發(fā)生、發(fā)展，提高DN患者的生活質(zhì)量。

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10.3969/j.issn.1002-7386.2016.21.038·綜述與講座·

項(xiàng)目來(lái)源：國(guó)家自然科學(xué)基金項(xiàng)目(編號(hào)：81400812)

054001河北省邢臺(tái)市第一醫(yī)院藥劑科(劉雪峰)；河北醫(yī)科大學(xué)第一醫(yī)院科研中心(張睿)

R 587.24

A

1002-7386(2016)21-3323-04

2016-04-12)