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Advances in Clinical Medicine
Vol. 13  No. 11 ( 2023 ), Article ID: 74911 , 8 pages
10.12677/ACM.2023.13112440

MIF在慢性肾脏病患者中发生心血管事件的 相关性

李思莹，刘珍

新疆医科大学第一附属医院肾脏病中心，新疆 乌鲁木齐

收稿日期：2023年10月8日；录用日期：2023年11月3日；发布日期：2023年11月8日

摘要

慢性肾脏病(CKD)现在被认为是心血管疾病(CVD)的独立危险因素。而慢性肾脏病发生心血管事件的机制主要包括：肾素–血管紧张素–醛固酮系统异常激活(RAAS)、氧化应激、炎症反应、组织纤维化、贫血、自主神经系统功能紊乱、尿毒症毒素、代谢紊乱等。对于慢性肾脏病患者并发心血管事件，巨噬细胞迁移抑制因子(MIF)在其中扮演什么角色仍然没有统一的结论。MIF仍是目前研究的热点炎症因子。

关键词

慢性肾脏病，心血管疾病，综述，MIF

The Correlation between MIF and Cardiovascular Events in Patients with Chronic Kidney Disease

Siying Li, Zhen Liu

Kidney Disease Center of The First Affiliated Hospital of Xinjiang Medical University, Urumqi Xinjiang

Received: Oct. 8th, 2023; accepted: Nov. 3rd, 2023; published: Nov. 8th, 2023

ABSTRACT

Chronic kidney disease (CKD) is now considered an independent risk factor for cardiovascular disease (CVD). The mechanisms of cardiovascular events in chronic kidney disease mainly include: abnormal activation of the renin angiotensin aldosterone system (RAAS), oxidative stress, inflammatory response, tissue fibrosis, anemia, dysfunction of the autonomic nervous system, uremic toxins, metabolic disorders, etc. There is still no unified conclusion on the role of macrophage migration inhibitory factor (MIF) in cardiovascular events in patients with chronic kidney disease. MIF is still a hot research topic for inflammatory factors.

Keywords:Chronic Kidney Disease, Cardiovascular Disease, Overview, MIF

Copyright © 2023 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

近10年来，全球范围内，慢性肾脏病(CKD)的患病率呈持续增长的趋势。根据卫生计量与评估研究所的数据，2016年，在15至49岁的男性中，由CKD造成的全球负担占全球死亡人数的1.94%，而这一数字在低收入国家要高得多 [1] 。而CKD作为心血管疾病的独立危险因素，同时心血管事件是CKD患者过早死亡的主要原因，甚至在其进展为终末期肾病之前，CVD进展率是人群的两倍 [2] 。作为炎症作用的热门因子巨噬细胞迁移抑制因子(MIF)，目前针对其在CKD患者中并发心血管事件展开了多项研究，其中包括Magdy Algowhary等人通过对90名心衰患者，及60名相匹配的对照组，采用PCR-RFLP方法证明了MIF可能导致心衰的可能性 [3] ；陈怡仁等人通过Na和Ca增加肺静脉心律失常，通过CaMKII信号传导的ROS激活实现失调，从而使MIF在其中推动炎症期间房颤的可能发生 [4] ；而慢性肾脏病就是以慢性炎症、氧化应激为特征的疾病，而通过实验证明CKD患者的循环血清MIF显著升高 [5] ，故为慢性肾脏病患者发生房颤提供证据；杨一宁等人通过招募1176名冠状动脉疾病患者和1120名对照，发现MIF基因中rs755622的CC基因型是冠状动脉疾病的易感因素 [6] ；刘彦等人通过将慢性肾衰竭患者分为CKD组、腹膜透析组及血液透析组，分别测量血清MIF及左心室质量指数(LVMI)，得出了慢性肾衰竭患者血清MIF明显高于健康对照组，而相应的左心室肥厚的患者的水平也显著升高 [7] 等等，揭示了MIF在CKD患者中发生心力衰竭、房颤、冠状动脉性心脏病及左心室肥厚的联系。因此，我将对MIF在CKD并发相关心血管事件的主要发病机制，包括氧化应激、炎症反应、组织纤维化做一综述。

【介绍】

MIF在多种细胞类型中表达，如淋巴细胞、单核细胞/巨噬细胞、树突状细胞、中性粒细胞、成纤维细胞、心肌细胞、神经元、生殖组织、脂肪细胞和激素分泌细胞 [8] - [17] 。MIF与不同的自身免疫和炎症疾病有关，包括败血症、类风湿性关节炎、肾小球肾炎、多发性硬化、动脉粥样硬化、经典皮肤迟发型超敏反应和急性呼吸窘迫综合征以及癌症 [15] [18] [19] [20] [21] [22] 。

2. CKD合并心血管事件的相关性

CKD是指各种原因引起的肾脏结构或功能异常 ≥ 3个月，包括出现肾脏损伤标志(白蛋白、尿沉渣异常、肾小管相关病变、组织学检查异常及影像学检查异常)或肾移植病史，伴或不伴肾小球滤过率(GFR)下降；或不明原因的GFR下降(<60 ml/min) ≥ 3个月。国际公认的慢性肾脏病分期按GFR将慢性肾脏病的分期及建议将慢性肾脏病分为1~5期。1期：GFR ≥ 90 (ml/min·1.73 m2)；2期：GFR范围在60~89 (ml/min·1.73 m2)；3a期：GFR范围在45~59 (ml/min·1.73 m2)；3b期：GFR范围在：30~44 (ml/min·1.73 m2)；4期：GFR范围在15~29 (ml/min·1.73 m2)；5期：GFR < 15 (ml/min·1.73 m2)或透析。根据美国卫生计量与评估研究所的数据显示：2016年，在15至49岁的男性中，由CKD造成的全球负担占全球死亡人数的1.94%，而这一数值在低收入国家要高得多 [1] 。2012年张露霞等研究发现CKD在我国成年人中的患病率为10.8% [23] 。而CKD合并心血管疾风险增加之间存在密切的关系，CKD作为心血管疾病的独立危险因素，同时心血管事件是CKD患者过早死亡的主要原因，甚至在其进展为终末期肾病之前，CVD进展率是人群的两倍 [2] 。大型队列研究表明，在校正了抑制的CVD危险因素、CVD事件史和蛋白尿后，CVD (急性冠状动脉综合征[ACS]、中风、心力衰竭和心源性猝死)和CKD之间存在强烈而独立的关联。在eGFR为45~59 ml/min/1.73 m2的患者中，风险增加了43%，而在eGFR < 5 ml/min/173 m2的人群中，风险则增加了343% [24] 。尽管GFR类别G5 (GFR 15 ml/min/1.73 m2)的人发生CVD事件的风险最高，但由于这些类别的患病率更高，GFR类别G3a-G3b (GFR 30~59 ml/min/173 m2)人群中会发生更多事件 [25] 。这些事件发生在CKD患者的较年轻年龄，表明CKD加速了CVD [26] 。CKD与心血管疾病有很多共同的危险因素，包括年龄、高血压、电解质紊乱、代谢综合征、分子信号通路等等 [27] [28] 。同时，两者的发病机制也存在着相同点，例如：氧化应激、炎症反应、自主神经功能紊乱、组织纤维化、代谢综合征、血流动力学紊乱等。而MIF在上述发病机制中发挥着重要的作用。

3. MIF在CKD合并CVD中氧化应激的作用

氧化应激在CKD及CVD中均扮演着重要的角色；有关MIF的实验中证明了，MIF在急性心肌缺血的体内和体外，氧化应激刺激心肌细胞分泌MIF [29] [30] [31] ；氧化应激的增加与CKD的进展阶段呈正相关 [29] [32] [33] ；研究证明，在CKD患者中血管紧张素II可以通过GRK2调控产生MIF [34] 。MIF可通过CD74/CD44 MIF受体复合物激活AMP激活蛋白激酶(MAPK)信号通路 [35] ，进而调节PI3K/Akt/Src信号级联转导 [36] [37] [38] ，而PI3K/Akt信号通路可以刺激一氧化氮(NO)的产生，进一步在心肌细胞中发挥着作用氧化应激反应。氧化应激的增加是动脉粥样硬化的关键特征之一，这导致内皮损伤/功能障碍、NO和NF-κB相关信号转导紊乱以及低密度脂蛋白(LDL)的氧化修饰 [39] 。脂质代谢紊乱是慢性肾脏病中常见的合并症，1997年Miyazaki等人首次将MIF的局部合成与脂质诱导损伤的发病机制联系起来研究 [40] ，这项研究表明了：高胆固醇血症导致肾小球内细胞MIF表达上调，这可能是脂质诱导肾损伤发展过程中的单核巨细胞募集和聚集的重要机制；同时，MIF可能在促进巨噬细胞聚集和随后脂质沉积部位动脉粥样硬化病变的发展中发挥着关键作用 [40] 。例如：Christin Krammer等人通过比较30周、42周及48周小鼠的MIF基因检测，发现MIF缺陷小鼠在30/24周龄和42/36周龄组中表现出动脉粥样硬化病变减少；同时也发现了MIF缺乏可促进年轻但未成年小鼠的病变巨噬细胞和T细胞计数，确定了MIF和衰老依赖性变化，主要与脂质合成和代谢，脂质储存和棕色脂肪细胞分化及免疫力和动脉粥样硬化相关的富集基因有关 [41] 。有实验通过MIF以一种衍生物MIF (cycl10)，在体外和体内/体外抑制例关键的炎症和致动脉粥样硬化MIF的活性，间接表明了MIF在动脉粥样硬化功能中起着关键作用 [42] ；李文强等人通过颈动脉斑块患者MIF-173G/C位点基因，得出MIF基因-173G/C位点多态性与颈动脉硬化密切相关，携带C基因是颈动脉粥样硬化斑块形成的危险因素，也证明可了MIF在动脉粥样硬化中发挥着重要的作用。而脂质的过氧化作用导致的动脉粥样硬化在心血管疾病中发挥着重要的作用。

4. MIF在CKD合并CVD中炎症反应作用

炎症反应在CKD患者CVD事件的发生中起着至关重要的作用。微炎症是只慢性、持续性、低度存在的炎症，而非病原微生物感染的结果 [43] 。在肾脏中，血管紧张素II (AngII)现在被认为是一种调节肾细胞反应的细胞因子，并参与肾脏疾病的几个过程，包括细胞损伤及炎症 [44] 。而MIF由一些肾小球上皮细胞和大约一半的皮质小管表达 [45] [46] ，而表达的MIF与肾功能障碍、组织学损伤和白细胞浸润显著相关 [47] 。Brown等人得出结论“受损肾脏内MIF产生的增加可以通过尿液MIF浓度的增加来反应” [48] 。CD74在多种组织损伤疾病中表达增加，如心脏缺血–再灌注损伤，阿尔兹海默症、动脉粥样硬化斑块、毒素诱导的肝纤维化和广泛的恶性细胞 [49] - [57] ，CD74可作为AngII与MIF的连接蛋白，在许多细胞类型中独立于MHC II类表达 [58] ，即血管紧张素II I型受体，同时也是巨噬细胞迁移抑制因子(MIF)的高亲和力受体 [59] 。AngII可以激活核因子κB (NF-κB)，进而刺激MIF的产生 [60] [61] ，而CD74与CD44的结合形成复合物后与MIF结合，可以导致多条细胞内信号通路，如细胞外信号调节酶(ERK) 1和2的激活、PI3K-Akt信号转导级联、NFjB和AMP激活蛋白激酶(AMPK)的激活 [59] 从而促进炎症反应。而炎症是导致心血管病理过程的一个主要危险因素，MIF通过调控的NF-κB调节基因包括多种炎性细胞因子，如白介素-1 (IL-1)、IL-6、TNF-α及干扰素-γ (IFN-γ) [39] 参与心血管事件的发生和发展，并且IL-1和TNF-α激活NF-κB从而形成反馈回路。锌是人体健康的必需营养素，具有抗氧化应激和抗炎作用 [62] ，膳食锌缺乏或细胞内锌缺乏已表明会导致培养细胞、动物模型和人类中NF-κB和NF-κ调节性炎性细胞因子的表达的激活 [63] [64] ，补充锌可能通过抑制IκB的磷酸化和降解来抑制NF-κB活化和NF-κ。一些研究表明CKD患者锌平衡为负 [65] [66] 。这可能是由于肠道吸收减少、食物摄入量减少、尿毒症性、生物利用度和/或缺失增加，如通过面部、尿液或血液透析等 [67] 。缺锌还与CVD事件相关的各种危险因素相关，如高血压、血脂异常、2型糖尿病、炎症和氧化应激 [67] 。锌已被证明可以阻断缺氧刺激的HIF-1α核异位，随后破坏HIF-1异二聚体，并诱导HIF-1α蛋白酶体降解 [68] 。另一方面，锌预处理可以诱导肾细胞中HIF基因的表达，包括HIF-1α [69] 。

5. MIF在CKD合并CVD中纤维化作用

在CKD中，足细胞的丢失及其ECM替代(称为肾小球硬化)、肾小管细胞损伤和随后的肾小管间质纤维化会导致肾单位丢 [70] [71] 。这些过程导致实质组织被ECM替代，细胞外基质(ECM)是纤维化的病理标志，并伴随着不可逆的损伤 [72] 。TGF-β是一种由肾脏中所有的细胞类型产生的强大的纤维化生长因子，其诱导纤维化的机制包括增强成纤维化细胞增殖和肌成纤维细胞转分化、ECM蛋白合成以及通过诱导蛋白酶抑制剂抑制MMP活性来保存基质 [73] 。TGF-β通过激活结缔组织生长因子刺激细胞增殖和ECM积累 [74] ，TGF-β通过Smad2/3H和p38丝裂原激活蛋白(MAP)激酶信号传导诱导EMT。除了成纤维作用外，TGF-β还导致肾小管上皮细胞凋亡和炎性细胞聚集。巨噬细胞的数量与衰老的主要标志 [75] [76] [77] [78] 。MIF可能通过TGF-β1/Smads信号通路抑制纤维化。成纤维细胞生长因子23 (FGF23)的重要水平在慢性肾脏病(CKD)中升高，并与左心室肥厚、心力衰竭和死亡密切相关 [79] 。CKD中FGF23的慢性升高与心力衰竭和死亡的发展独立相关 [80] - [85] 。

6. 结论

MIF可以通过多种途径参与CKD基础上并发心血管事件，其中促进的机制比较复杂，且机制之间相互影响，共同促进。对MIF在CKD合并CKD患者的病理生理机制有助于进一步筛选早期CKD患者并发心血管事件的发生及发展。通过对MIF在其病理生理机制的研究，为CKD合并血管患者提供治疗方案的可能性。

文章引用

李思莹,刘 珍. MIF在慢性肾脏病患者中发生心血管事件的相关性
The Correlation between MIF and Cardiovascular Events in Patients with Chronic Kidney Disease[J]. 临床医学进展, 2023, 13(11): 17420-17427. https://doi.org/10.12677/ACM.2023.13112440

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