miRNA-21在糖尿病肾病中的作用机制及研究进展
The Mechanism and Research Progress of miRNA-21 in Diabetic Kidney Disease
DOI: 10.12677/ACM.2021.1112915, PDF, HTML, XML,  被引量   
作者: 刘 静:西安医学院,陕西 西安;张 鹏*:第四军医大学西京医院肾内科,陕西 西安
关键词: 糖尿病肾病miRNA-21作用机制Diabetic Kidney Disease MicroRNA-21 Mechanism of Action
摘要: 糖尿病肾病(DKD)是糖尿病引起的严重微血管并发症,其发病机制复杂且临床上缺乏高度敏感的诊断标志物。目前学者们对DKD的发病机制和可能的治疗方法进行了大量的研究,但临床上仍缺乏有效的治疗手段从而预防患者进展至终末期肾脏病(ESRD)。近年来,miRNA-21在DKD中异常表达并且通过调控内皮细胞与足细胞结构与功能、炎症反应、氧化应激、肾小管间质纤维化及代谢途径等环节参与DKD进展已被广泛证实。深入研究miRNA-21在DKD中的作用机制,以期为寻找DKD的早期诊断标志物和靶向治疗提供新思路。
Abstract: Diabetic kidney disease (DKD) is a serious microvascular complication caused by diabetes with complex pathogenesis and lack of highly sensitive diagnostic markers in clinic. Currently, researchers have conducted a large number of studies on the pathogenesis and possible treatment methods of DKD, but there is still a lack of effective treatment methods to prevent patients from progressing to end-stage renal disease (ESRD). In recent years, it has been widely confirmed that miRNA-21 is abnormally expressed in DKD and plays a role in the progression of DKD by regulating the structure and function of endothelial cells and podocytes, inflammatory response, oxidative stress, renal tubulointerstitial fibrosis and metabolic pathways. Further study on the mechanism of miRNA-21 in DKD is expected to provide new ideas for searching for early diagnostic markers and targeted therapy of DKD.
文章引用:刘静, 张鹏. miRNA-21在糖尿病肾病中的作用机制及研究进展[J]. 临床医学进展, 2021, 11(12): 6169-6176. https://doi.org/10.12677/ACM.2021.1112915

1. 引言

糖尿病是一种以血糖高为特征的进展性代谢性疾病,会造成人体心、眼、肾、皮肤等多器官系统损害。据最新数据,目前全球有4亿人受糖尿病的困扰,估计到2045年全世界患病人数将达到6.93亿 [1],已经成为严重威胁人们健康的主要疾病之一。糖尿病肾病(Diabetic Kidney Disease, DKD)是糖尿病引起的慢性肾脏疾病,以白蛋白尿和肾小球滤过率逐渐下降为主要特征。研究显示,DKD已经超过慢性肾小球肾炎成为导致终末期肾功能衰竭(End-stage renal disease, ESRD)的主要原因,也是糖尿病患者致死的主要原因之一。糖尿病发展至后期进行肾脏替代治疗及相关并发症的治疗成为家庭乃至社会沉重的经济负担。DKD早期的形态学改变主要为肾小球和肾小管肥大、肾小球基底膜(glomerular basement membrane, GBM)增厚、足突融合、系膜基质扩张等;后期发展为不同程度的肾小管间质纤维化,最终致肾功能丧失 [2]。Roy等 [3] 发现miRNA-21可参与调节DKD相关的系膜扩张、足细胞丢失、蛋白尿、炎症基因表达和间质纤维化,在调控糖尿病及其相关的肾损害方面发挥重要作用。本文现就miRNA-21在糖尿病肾病中作用机制和研究进展作一综述,以期更好的防治糖尿病肾病的发生和发展。

2. miRNA-21概述

1993年由Lee等人首次发现miRNA后,miRNAs就成为人们研究的热点。它高度保守并且在人体中大量存在,其主要通过碱基互补配对的方式特异性识别靶基因,从而调控基因的表达,参与生物体的生长发育、细胞的增殖分化、肿瘤的发生发展和调控脏器损伤及纤维化。

miRNA被认为在糖尿病发病机制中具有重要的生物学意义,并且调控着相应的分子信号通路。其中miRNA-21是一种重要的miRNA,在各种疾病中经常呈高丰度表达,提示其在细胞增殖和凋亡中发挥重要作用 [4]。miRNA-21广泛存在于哺乳动物的细胞、组织、器官和血液,并且因其在循环系统中的稳定性、组织特异性、高度保守性,使之成为糖尿病肾损害潜在的诊断和治疗靶点。

3. miRNA-21与糖尿病

研究发现,miRNA-21是一种炎症介质,在很多疾病中发挥促炎作用 [5],在糖尿病中可能通过促炎症因子表达而介导糖尿病的发生及发展。miRNA-21通过抑制磷酸酶及张力蛋白同源物(phosphatase and tensin homolog, PTEN)的磷酸化,诱导足细胞血管内皮生长因子(vascular endothelial growth factor, VEGF)高表达,进而破坏足细胞形态 [6];通过靶向促进细胞周期阻滞使肾小球系膜细胞肥大,损害肾小球滤过屏障。动物实验发现通过下调小鼠胰岛β细胞中miRNA-21水平能够减轻胰岛素抵抗,改善脂质代谢紊乱 [7],从而延缓糖尿病的进展。也有学者发现 [8] [9],下调miRNA-21可减轻高糖诱导的炎症反应及足细胞凋亡,还可保护血管内皮细胞功能,进而减缓与糖尿病相关的微血管并发症的发展病程。

3.1. miRNA-21在糖尿病中高表达

miRNA-21在正常肾脏组织中呈低表达,而在急性肾损伤(AKI)和慢性肾脏病(CKD)患者的外周血和肾脏组织中均高表达,DKD动物模型中亦呈高丰度表达。高血糖大鼠与健康的大鼠相比,高血糖会引起miRNA-21的高表达。Liu L等 [10] 发现,在构建的体内糖尿病大鼠模型和体外高糖诱导下的NRK-52E模型中miRNA-21均显著升高。Chen等 [8] 发现,miRNA-21在DKD患者的血液和肾脏组织、由链脲佐菌素诱导的DKD大鼠的肾脏组织均表达上调。Wang Y等 [11] 通过在体内(链脲佐菌素诱导的糖尿病大鼠模型)和体外(高糖条件下的NRK-52E模型系统)也发现miRNA-21升高,并伴有E-钙粘蛋白降低和α-平滑肌肌动蛋白、胶原蛋白升高。这些都表明长期的高糖刺激会使肾脏组织中的miRNA-21明显升高。

3.2. miRNA-21高表达促进糖尿病发展

3.2.1. miRNA-21高表达与内皮细胞功能

肾小球滤过屏障的主要组成部分即为肾小球内皮细胞,内皮细胞可以动态地调节微血管的渗透作用,但其易受循环物质的直接影响,比如高血糖、高血脂及炎症介质都会损害内皮细胞功能。Gilbert等 [12] 发现长期的高血糖刺激会致肾小球内皮细胞损伤,进而产生蛋白尿等一系列临床症状。此外,肾小球内皮细胞可分泌多种血管活性物质和细胞因子,进而调节肾小球的滤过功能 [13]。内皮细胞功能障碍与NO及内皮型一氧化氮合酶(endothelial nitric oxide synthase, eNOS)水平降低会使miRNA-21呈高表达 [14]。并且NO生成减少和生物利用度降低很大程度上会使糖尿病患者血管内皮功能障碍进一步加重,进而使miRNA-21上调 [15]。miRNA-21的高表达通过下调基质金属蛋白酶组织抑制因子(tissue inhibitor of metalloproteinase, TIMP) 3与血管内皮钙粘蛋白(vascular endothelial cadherin, VE cadherin)表达,而促进基质金属蛋白酶9 (matrix metalloprotein 9, MMP 9)的表达使血管内皮细胞通透性增加,从而破坏血管内皮屏障功能 [16]。内皮细胞的结构和功能紊乱使miRNA-21高表达,而miRNA-21高表达又进一步加重内皮细胞的损害。

3.2.2. miRNA-21高表达与足细胞和系膜细胞

足细胞是肾小球滤过屏障的结构基础,而系膜细胞是可以分泌细胞外基质、产生多种细胞因子以及具有收缩功能的肾脏固有细胞。Kölling等 [17] 研究显示,肾小球系膜细胞的肥大与miRNA-21在系膜细胞中高表达密切相关,miRNA-21通过靶向调控细胞分裂周期因子25A (cell division cycle 25 homolog A, Cdc25a)和周期蛋白依赖性激酶6 (cyclin-dependent kinase 6, Cdk6),抑制细胞周期的进程,进而导致肾小球系膜细胞增生肥大。还有学者研究报道,在高糖刺激下小鼠肾小球系膜细胞中miRNA-21上调,并且有明显的I型胶原沉着,肾间质出现严重纤维化,系膜细胞的结构与功能都受到严重损伤 [18]。在高糖环境中miRNA-21在系膜细胞中呈高表达,而miRNA-21通过靶向调控促进细胞周期阻滞,损害系膜细胞结构功能。体外实验发现在高糖处理的足细胞中,TIMP3是miRNA-21的一个作用靶点,TIMP3表达上调能减轻高糖诱导足细胞凋亡,而miRNA-21上调可抑制TIMP3表达进而加重足细胞凋亡 [8]。miRNA-21还可靶向作用于PTEN,PTEN可通过抑制Akt的活化从而减轻肾脏足细胞的表型变化,还可通过抑制PI3K/Akt通路减轻肾脏足细胞损害,而miRNA-21高表达则通过抑制PTEN从而破坏足细胞形态 [19]。同时体内实验证明,通过拮抗miRNA-21可以显著改善足细胞的损伤。miRNA-21高表达损害足细胞与系膜细胞的结构与功能,加快DKD病程。

4. miRNA-21与糖尿病肾病

DKD是糖代谢异常引起的一种严重微血管病变,最主要的病理特征是弥漫性肾小球硬化、eGFR下降、细胞外基质沉积(extracellular matrix, ECM)及肾小管间质纤维化等,这些都使肾功能进行性丧失。而高血糖、炎症反应和氧化应激等因素均可推进糖尿病病理损害的进程。研究表明,miRNA-21在DKD小鼠肾小管上皮细胞中广泛分布 [20]。并且miRNA-21的许多靶点都与DKD有关,在DKD和肾纤维化的发病机制中起着重要作用 [21] [22] [23]。由以往研究已知,尿白蛋白/肌酐比(albumin creatinine rate, ACR)、肌酐清除率(creatinine clearance rate, Ccr)、肾小球体积和胶原纤维含量等都是评价DKD肾脏功能和结构受损的准确指标;有报道,血清miRNA-21的表达程度与ACR、肾小球体积和胶原纤维含量水平呈显著正相关,而与Ccr呈负性相关,表明血清miRNA-21的上调或下调,能间接地反映肾脏的结构与功能,血清miRNA-21可能在DKD早期诊断中起重要作用 [20]。

4.1. miRNA-21在糖尿病肾病中高表达

Wang等 [24] 在利用糖尿病和非糖尿病小鼠肾脏总RNA进行基因组miRNA表达分析时,发现miRNA-21是受调控程度最高的miRNA。而且随着DKD的进展,血清和肾组织miRNA-21显著升高,相关性分析提示血清miRNA-21的水平与肾组织miRNA-21水平之间呈显著正相关 [20]。McClelland等 [25] 通过对各种肾脏纤维化疾病模型和糖尿病体外实验分析证实,存在肾小管miRNA-21表达增多,并且miRNA-21表达上调与DKD中肾脏纤维化的程度、机体肾功能下降速率呈明显正相关,提示miRNA-21高表达可以促进糖尿病肾病的发展。

4.2. miRNA-21高表达促进糖尿病肾损害

4.2.1. miRNA-21高表达通过炎症反应及氧化应激加重糖尿病肾损害

在机体处于糖尿病状态时,糖在体内大量蓄积,使糖类代谢超负荷,从而导致活性氧(reactive oxygen species, ROS)产生过多。高糖环境下产生的ROS可以介导多种与糖尿病肾病相关的炎性因子,如白细胞介素-1β (interleukin-1β, IL-1β)、肿瘤坏死因子(tumor necrosis factor α, TNF-α)及转化生长因子-β (transforming growth factor β, TGF-β)和核转录因子-κB (nuclear factor-κB, NF-κB)等相关因子 [26]。DKD的病程与全身及肾脏局部的炎症反应相关。IL、TNF、单核细胞趋化蛋白(monocyte chemoattractant protein, MCP)、巨噬蛋白炎性蛋白(macrophage inflammatory protein, MIP)、免疫介质和黏附分子水平会随着疾病的进展而增加 [27]。这些炎性因子在糖尿病肾病的形成过程中有促进性的关系。大量炎症因子长时间高表达会推动成纤维细胞合成细胞外基质增多,从而推动肾脏纤维化的进展 [28]。Petrica等 [29] 发现2型糖尿病(type 2 diabetes, T2DM)患者发生DKD时的血清和尿液中ILs (IL-α、IL-8、IL-18)均与miRNA-21密切相关。并且外周血来源外泌体中miRNA-21表达水平与IL-6、IL-1呈正相关 [30]。miRNA-21在炎症反应中发挥着动态作用,单核细胞中的miRNA-21由LPS刺激诱导,并抑制NF-κB信号通路的激活 [31]。

Fleissner等 [32] 发现,非对称二甲基精氨酸(ADMA)会使内皮祖细胞miRNA-21表达上调,通过抑制内皮祖细胞中SOD2表达而增加活性氧,加剧氧化应激损害。miRNA-21高表达可加剧氧化应激,而拮抗miRNA-21后氧化应激减弱。人源性激肽释放酶结合蛋白(Kallistatin, KS)通过肝素结合位点使miRNA-21表达下调,并且通过调控蛋白激酶B (protein kinase B, PKB/Akt)-NF-κB通路减轻炎症反应和减少ROS形成 [33]。miRNA-21在氧化应激与炎症反应的协同作用下,进一步加快了糖尿病肾病的病程。

4.2.2. miRNA-21高表达可以通过代谢途径加重糖尿病肾损害

miRNA-21高表达可以通过调节过氧化物酶体增殖物激活受体α (peroxisome proliferators-activated receptors α, PPAR-α)相关脂质代谢途径进而推动DKD病程。Chau等 [34] 通过基因表达谱分析证实miRNA-21可上调代谢途径相关基因群,比如miRNA-21可直接靶向调控PPAR-α的脂质代谢途径,miRNA-21高表达可下调PPAR-α通路下游线粒体中的抗氧化蛋白MPV17I,减少线粒体和过氧化物酶体的合成,而促进活性氧的产生,加重肾损伤。Chung等 [35] 发现miRNA-21还可以诱导PPAR-α沉默,影响脂质代谢过程从而增加脂质累积和加重肾纤维化程度,拮抗miRNA-21可明显改善脂质积累和肾脏纤维化。最新研究表明 [7] miRNA-21 antagomir可下调TG、TC、LDL-Cho含量,上调HDL-Cho含量,且改善了链脲佐菌素诱导的T2DM大鼠的脂质代谢紊乱。拮抗miRNA-21明显改善脂质累积和肾脏纤维化,减慢DKD病程进展。

4.3. miRNA-21高表达加重肾小管间质纤维化

肾间质纤维化是DKD发展至后期的结果,而肾小管上皮细胞间充质转化(epithelial mesenchymal transition, EMT)和细胞外基质(extracellular matrix, ECM)沉积是肾脏纤维化的特征表现。在糖尿病肾脏损害病程中,高血糖、TNF-α和TGF-β等都是miRNA-21上调的原因,miRNA-21水平上调可以通过调控TGF-β/Smads、NF-κB、PTEN/Akt等通路进而调节与胞外基质沉积和上皮细胞间充质转化相关的E-钙粘蛋白(E-cadherin)、α平滑肌肌动蛋白(α smooth muscle actin, α-SMA)、胶原蛋白(I,III,IV型)和纤维连接蛋白(fibronectin, FN)等基因表达,进而导致肾脏纤维化加重,而拮抗miRNA-21可减缓肾脏纤维化 [36] [37]。Zhong等 [38] 研究得知,miRNA-21靶向调控Smad7,而Smad7是通过抑制TGF-β和NF-κB信号通路,在敲除miRNA-21后,Smad7表达较之前上调,肾脏纤维化程度也随之减轻。TGF-β1/Smad2/3信号通路是DKD肾脏纤维化形成的公认途径。TGF-β1与受体结合后,通过Smad2、Smad3两个下游介质传出信号,诱导肾小管上皮细胞发生EMT,进而促进胞外基质的产生和沉积,最终导致肾组织广泛纤维化,上述整个过程受到Smad7的负反馈调节,与miRNA-21靶向调控Smad7形成一个闭合环路。Wang [11] 发现,miRNA-21通过TGF-β1/Smads信号通路使ECM沉积增多、α-SMA高表达,促进肾脏纤维化进展。Zhong等 [39] 研究发现,在糖尿病小鼠模型db/db小鼠中,与同龄的db/m(+)小鼠相比,20周时其肾脏miRNA-21表达增多了两倍,并且与微量白蛋白尿、肾纤维化和炎症的发展有关,在10周时将miRNA-21敲除质粒快速转移到db/db小鼠肾脏中,20周时发现其尿微量白蛋白减少,肾纤维化程度和炎症反应减轻,这表明调控miRNA-21表达有治疗糖尿病肾病的潜力。Sun发现 [40] 在活化的成纤维细胞中miRNA-21呈现高表达,并且miRNA-21与程序性细胞死亡因子4 (progrmammed cell death 4, PDCD4)及转录激活蛋白1 (activation protein 1, AP-1)之间形成的反馈环可以使miRNA-21的表达持续维持在高水平;而miRNA-21的高表达使TGF-β/Smad信号通路传导加快,负反馈促进成纤维细胞的活化。miRNA-21高表达通过调控PTEN/Akt相关通路也可以加速糖尿病肾损害的病理进程。高糖可通过Notchl/Hesl信号通路下调PTEN表达以抑制自噬,从而促进DKD的肾小管间质纤维化 [41]。研究显示 [42],miRNA-21可被损伤的肾小管上皮细胞分泌,并通过微泡递送的方式进入肾小管上皮细胞中,miRNA-21在肾小管高表达并通过抑制PTEN而增强Akt信号传导,导致Akt的激活与磷酸化,促使肾小管表型转变和基质沉积,加重肾脏纤维化。

4.4. miRNA-21高表达损害肾小球滤过屏障

糖尿病肾病主要肾脏结构改变是肾小球内皮细胞结构破坏,肾小球和肾小管间质内皮细胞减少和毛细血管损伤,进而导致肾小球滤过功能逐渐丧失。DKD时肾小球滤过屏障损伤,就会导致蛋白质漏出,因肾小管重吸收能力降低且超过了其重吸收阈值,从而产生大量蛋白尿。Wang等 [43] 研究发现,在高糖环境中,小鼠血液及肾脏中miRNA-21表达均上调,miRNA-21上调促进足细胞去分化,并且使β-链蛋白(β-catenin)、TGF-β1和Smad3呈高表达,而抑制Smad7表达。Kölling等 [17] 发现miRNA-21介导着足细胞足突的收缩与扩张进而改变裂孔的大小和滤过膜的面积,提示miRNA-21参与蛋白尿形成。抑制miRNA-21表达可以减轻足细胞损伤和尿白蛋白丢失,提示拮抗miRNA-21对足细胞具有保护作用。Wang等 [20] 发现血清miRNA-21与肾小球基底膜厚度、肾小球体积呈显著正相关。既往报道 [44],在肾小球内皮细胞中的miRNA-21的水平与UACR呈正相关,而与Ccr水平呈负性相关,抑制miRNA-21表达可显著提高肌酐清除率和降低蛋白尿,保护肾血管内皮屏障的结构与功能。

5. 小结

综上所述,miRNA-21参与了糖尿病及糖尿病肾病病程的各个阶段。miRNA-21在糖尿病患者或动物模型的组织或血液中均呈高表达,并且通过损害内皮细胞与足细胞结构功能、促进系膜细胞增生肥大等途径进一步促进糖尿病进展。氧化应激、炎症反应、糖基化终产物等激活NF-κB使大量促炎因子释放,加重肾脏局部炎症、上皮间充质转化、纤维化等病理过程;miRNA-21靶向调控PPAR-α的脂质代谢途径进一步加重脂质累积和肾脏纤维化。miRNA-21通过调控TGF-β/Smads、NF-κB、PTEN/Akt等通路加重肾脏纤维化,破坏肾小球滤过屏障,损害肾功能,进而推动糖尿病肾病进展。

随着对miRNA-21及糖尿病肾病的深入研究,目前已经证实拮抗miRNA-21可以改善DKD的进程。未来还需要更多的针对miRNA-21治疗糖尿病肾病分子机制的研究,进而为糖尿病肾病的诊断和治疗提供更多的思路。

致谢

这是个日新月异,各行各业欣欣向荣的年代,每个人即是参与者,也是推动者。作为医学生更要开拓创新,努力钻研新技术,学习新知识。

在这里我要由衷地感谢所有帮助过我,支持过我的老师,同学,朋友,家人。首先,我要感谢我的导师张鹏教授。对于病人来讲他是一位医术精湛,耐心细致的好医生;对于学生来讲,他是一位尽职尽责,诲人不倦的好老师。感谢您关心并指导我的研究进展,督促我学习。正是导师对我的不断鞭策和教诲,我才能快速成长起来。其次,我还要感谢我的父母、朋友,感谢他们无论在学习方面还是生活方面都给予我无微不至的关怀。

人生就是一段段的旅途,旅程的意义是让我们领略美好的风景,同时变成更好的自己。

NOTES

*通讯作者。

参考文献

[1] Cho, N.H., Shaw, J.E., Karuranga, S., et al. (2018) IDF Diabetes Atlas: Global Estimates of Diabetes Prevalence for 2017 and Projections for 2045. Diabetes Research and Clinical Practice, 13, 271-281.
https://doi.org/10.1016/j.diabres.2018.02.023
[2] Niewczas, M.A., Pavkov, M.E., Skupien, J., et al. (2019) A Signature of Circulating Inflammatory Proteins and Development of End-Stage Renal Disease in Diabetes. Nature Medicine, 25, 805-813.
https://doi.org/10.1038/s41591-019-0415-5
[3] Roy, D., Modi, A., Khokhar, M., et al. (2021) MicroRNA 21 Emerging Role in Diabetic Complications: A Critical Update. Current Diabetes Reviews, 17, 122-135.
https://doi.org/10.2174/1573399816666200503035035
[4] Sekar, D., Venugopal, B., Sekar, P., et al. (2016) Role of microRNA 21 in Diabetes and Associated/Related Diseases. Gene, 582, 14-18.
https://doi.org/10.1016/j.gene.2016.01.039
[5] Zhao, M., Zhu, N., Hao, F. and Song, Y. (2019) The Regulatory Role of Non-Coding RNAs on Programmed Cell Death Four in Inflammation and Cancer. Frontiers in Oncology, 18, 9-19.
https://doi.org/10.3389/fonc.2019.00919
[6] Haque, R., Iuvone, P.M., He, L., et al. (2017) The MicroRNA-21 Signaling Pathway Is Involved in Prorenin Receptor (PRR)-Induced VEGF Expression in ARPE-19 Cells under a Hyperglycemic Condition. Molecular Vision, 14, 251-262.
[7] Wang, Y., Yang, L.Z., Yang, D.G., et al. (2020) MiR-21 Antagomir Improves Insulin Resistance and Lipid Metabolism Disorder in Streptozotocin-Induced Type 2 Diabetes Mellitus Rats. Annals of Palliative Medicine, 9, 394-404.
https://doi.org/10.21037/apm.2020.02.28
[8] Chen, X., Zhao, L., Xing, Y., et al. (2018) Down-Regulation of microRNA-21 Reduces Inflammation and Podocyte Apoptosis in Diabetic Nephropathy by Relieving the Repression of TIMP3 Expression. Biomedicine & Pharmacotherapy, 108, 7-14.
https://doi.org/10.1016/j.biopha.2018.09.007
[9] Liu, Y., Luo, F., Wang, B., et al. (2016) STAT3-Regulated Exosomal miR-21 Promotes Angiogenesis and Is Involved in Neoplastic Processes of Transformed Human Bronchial Epithelial Cells. Cancer Letters, 370, 125-135.
https://doi.org/10.1016/j.canlet.2015.10.011
[10] Liu, L., Wang, Y., Yan, R., et al. (2019) BMP-7 Inhibits Renal Fibrosis in Diabetic Nephropathy via miR-21 Downregulation. Life Sciences, 238, Article ID: 116957.
https://doi.org/10.1016/j.lfs.2019.116957
[11] Wang, Y., Liu, L., Peng, W., et al. (2019) Ski-Related Novel Protein Suppresses the Development of Diabetic Nephropathy by Modulating Transforming Growth Factor-β Signaling and microRNA-21 Expression. Journal of Cellular Physiology, 234, 17925-17936.
https://doi.org/10.1002/jcp.28425
[12] Gilbert, R.E. (2014) The Endothelium in Diabetic Nephropathy. Current Atherosclerosis Reports, 16, 410.
https://doi.org/10.1007/s11883-014-0410-8
[13] Maezawa, Y., Takemoto, M. and Yokote, K. (2015) Cell Biology of Diabetic Nephropathy: Roles of Endothelial Cells, Tubulointerstitial Cells and Podocytes. Journal of Diabetes Investigation, 6, 3-15.
https://doi.org/10.1111/jdi.12255
[14] Cengiz, M., Yavuzer, S., Kılıçkıran Avcı, B., et al. (2015) Circulating miR-21 and eNOS in Subclinical Atherosclerosis in Patients with Hypertension. Clinical and Experimental Hypertension, 37, 643-649.
https://doi.org/10.3109/10641963.2015.1036064
[15] Takahashi, T. and Harris, R.C. (2014) Role of Endothelial Nitric Oxide Synthase in Diabetic Nephropathy: Lessons from Diabetic eNOS Knockout Mice. Journal of Diabetes Research, 2014, 590-541.
https://doi.org/10.1155/2014/590541
[16] Dai, J., Chen, W., Lin, Y., et al. (2017) Exposure to Concentrated Ambient Fine Particulate Matter Induces Vascular Endothelial Dysfunction via miR-21. International Journal of Biological Sciences, 13, 868-877.
https://doi.org/10.7150/ijbs.19868
[17] Kölling, M., Kaucsar, T., Schauerte, C., et al. (2017) Therapeutic miR-21 Silencing Ameliorates Diabetic Kidney Disease in Mice. Molecular Therapy, 25, 165-180.
https://doi.org/10.1016/j.ymthe.2016.08.001
[18] Lu, X., Fan, Q., Xu, L., et al. (2015) Ursolic Acid Attenuates Diabetic Mesangial Cell Injury through the Up-Regulation of Autophagy via miRNA-21/PTEN/Akt/mTOR Suppression. PLoS ONE, 10, 117-400.
https://doi.org/10.1371/journal.pone.0117400
[19] Li, X.Y., Wang, S.S., Han, Z., et al. (2017) Triptolide Restores Autophagy to Alleviate Diabetic Renal Fibrosis through the miR-141-3p/PTEN/Akt/mTOR Pathway. Molecular Therapy Nucleic Acids, 9, 48-56.
https://doi.org/10.1016/j.omtn.2017.08.011
[20] Wang, J., Duan, L., Tian, L., et al. (2016) Serum miR-21 May Be a Potential Diagnostic Biomarker for Diabetic Nephropathy. Experimental and Clinical Endocrinology & Diabetes, 124, 417-423.
https://doi.org/10.1055/s-0035-1565095
[21] Masoudi, M.S., Mehrabian, E. and Mirzaei, H. (2018) MiR21: A Key Player in Glioblastoma Pathogenesis. Journal of Cellular Biochemistry, 119, 1285-1290.
https://doi.org/10.1002/jcb.26300
[22] Wu, H., Kong, L., Zhou, S., et al. (2014) The Role of microRNAs in Diabetic Nephropathy. Diabetes Research, 2014, Article ID: 920134.
https://doi.org/10.1155/2014/920134
[23] Bhatt, K., Kato, M. and Natarajan, R. (2016) Mini-Review: Emerging Roles of microRNAs in the Pathophysiology of Renal Diseases. The American Journal of Physiology—Renal Physiology, 310, F109-F118.
https://doi.org/10.1152/ajprenal.00387.2015
[24] Wang, J.Y., Gao, Y.B., Zhang, N., et al. (2014) Tongxinluo Ameliorates Renal Structure and Function by Regulating miR-21-Induced Epithelial-to-Mesenchymal Transition in Diabetic Nephropathy. The American Journal of Physiology—Renal Physiology, 306, F486-F495.
https://doi.org/10.1152/ajprenal.00528.2013
[25] McClelland, A.D., Herman-Edelstein, M., Komers, R., et al. (2015) miR-21 Promotes Renal Fibrosis in Diabetic Nephropathy by Targeting PTEN and SMAD7. Clinical Science, 129, 1237-1249.
https://doi.org/10.1042/CS20150427
[26] Matoba, K., Takeda, Y., Nagai, Y., et al. (2019) Unraveling the Role of Inflammation in the Pathogenesis of Diabetic Kidney Disease. International Journal of Molecular Sciences, 20, 3393.
https://doi.org/10.3390/ijms20143393
[27] Perlman, A.S., Chevalier, J.M., Wilkinson, P., et al. (2015) Serum Inflammatory and Immune Mediators Are Elevated in Early Stage Diabetic Nephropathy. Annals of Clinical & Laboratory Science, 45, 256-263.
[28] Meng, X.M. (2019) Inflammatory Mediators and Renal Fibrosis. Advances in Experimental Medicine and Biology, 1165, 381-406.
https://doi.org/10.1007/978-981-13-8871-2_18
[29] Petrica, L., Milas, O., Vlad, M., et al. (2019) Interleukins and miRNAs Intervene in the Early Stages of Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients. Biomarkers in Medicine, 13, 1577-1588.
https://doi.org/10.2217/bmm-2019-0124
[30] Adela, R., Reddy, P.N.C., Ghosh, T.S., et al. (2019) Serum Protein Signature of Coronary Artery Disease in Type 2 Diabetes Mellitus. Journal of Translational Medicine, 17, 17.
https://doi.org/10.1186/s12967-018-1755-5
[31] Wynn, T.A., et al. (2007) Common and Unique Mechanisms Regulate Fibrosis in Various Fibroproliferative Diseases. Journal of Clinical Investigation, 117, 524-529.
https://doi.org/10.1172/JCI31487
[32] 张舒媛, 王东超, 李博, 等. 糖尿病肾病研究进展[J]. 世界中医药, 2015, 10(10): 1621-1625.
[33] Chao, J., Guo, Y., Li, P., et al. (2017) Role of Kallistatin Treatment in Aging and Cancer by Modulating miR-34a and miR-21 Expression. Oxidative Medicine and Cellular Longevity, 2017, Article ID: 5025610.
https://doi.org/10.1155/2017/5025610
[34] Chau, B.N., Xin, C., Hartner, J., et al. (2012) MicroRNA-21 Promotes Fibrosis of the Kidney by Silencing Metabolic Pathways. Science Translational Medicine, 4, 121ra18.
https://doi.org/10.1126/scitranslmed.3003205
[35] Chung, K.W., Lee, E.K., Lee, M.K., et al. (2018) Impairment of PPARα and the Fatty Acid Oxidation Pathway Aggravates Renal Fibr Dosis during Aging. American Society of Nephrology, 29, 1223-1237.
https://doi.org/10.1681/ASN.2017070802
[36] Wang, J.Y., Gao, Y.B., Zhang, N., et al. (2014) miR-21 Overexpression Enhances TGF-β1-Induced Epithelial-to-Mesenchymal Transition by Target smad7 and Aggravates Renal Damage in Diabetic Nephropathy. Molecular and Cellular Endocrinology, 392, 163-172.
https://doi.org/10.1016/j.mce.2014.05.018
[37] Zhong, X., Chung, A.C., Chen, H.Y., et al. (2013) miR-21 Is a Key Therapeutic Target for Renal Injury in a Mouse Model of Type 2 Diabetes. Diabetologia, 56, 663-674.
https://doi.org/10.1007/s00125-012-2804-x
[38] Wu, X., Ding, X., Ding, Z., et al. (2018) Total Flavonoids from Leaves of Carya Cathayensis Ameliorate Renal Fibrosis via the miR-21/Smad7 Signaling Pathway. Cellular Physiology and Biochemistry, 49, 1551-1563.
https://doi.org/10.1159/000493458
[39] Lan, H.Y. and Chung, A.C.K. (2011) Transforming Growth Factor-β and Smads. Contributions to Nephrology, 170, 75-82.
https://doi.org/10.1159/000324949
[40] Sun, Q., Miao, J., Luo, J., et al. (2018) The Feedback Loop between miR-21, PDCD4 and AP-1 Functions as a Driving Force for Renal Fibrogenesis. Journal of Cell Science, 131, jcs202317.
https://doi.org/10.1242/jcs.202317
[41] Liu, X., Zhang, Y., Shi, M., et al. (2018) Notch1 Regulates PTEN Expression to Exacerbate Renal Tubulointerstitial Fibrosis in Diabetic Nephropathy by Inhibiting Autophagy via Interactions with Hes1. Biochemical and Biophysical Research Communications, 497, 1110-1116.
https://doi.org/10.1016/j.bbrc.2018.02.187
[42] Zhou, Y., Xiong, M., Fang, L., et al. (2013) miR-21-Containing Microvesicles from Injured Tubular Epithelial Cells Promote Tubular Phenotype Transition by Targeting PTEN Protein. The American Journal of Pathology, 183, 1183-1196.
https://doi.org/10.1016/j.ajpath.2013.06.032
[43] Wang, X., Gao, Y., Tian, N., et al. (2018) Astragaloside IV Improves Renal Function and Fibrosis via Inhibition of miR-21-Induced Podocyte Dedifferentiation and Mesangial Cell Activation in Diabetic Mice. Drug Design, Development and Therapy, 12, 2431-2442.
https://doi.org/10.2147/DDDT.S170840
[44] Wang, J., Gao, Y., Ma, M., et al. (2013) Effect of miR-21 on Renal Fibrosis by Regulating MMP-9 and TIMP1 in kk-ay Diabetic Nephropathy Mice. Cell Biochemistry and Biophysics, 67, 537-546.
https://doi.org/10.1007/s12013-013-9539-2