Abstract：Peritoneal fibrosis related to peritoneal dialysis has become the main reason for peritoneal loss of performance and leading to the withdrawal of patients from peritoneal dialysis. Therefore, it is necessary to develop a new peritoneal dialysis fluid for the delay and treatment of peritoneal fibrosis. This review focuses on the pathogenesis of peritoneal fibrosis and the recent progress in the treatment of this disease
关键字：腹膜透析、腹膜纤维化、抗纤维化
Key word：Peritoneal dialysis, peritoneal fibrosis, anti fibrosis
长时间腹膜透析的腹膜病变的特点是间皮细胞丢失减少，间质纤维化导致间皮下致密带扩大，并伴有血管结构和数量的变化[1]。
腹膜纤维化的发生机制
1.1 炎症刺激 腹膜炎症和血管生成是腹膜纤维化发病的主要机制，腹膜炎症是由炎症触发的MCs（间皮细胞）的EMT，促使腹膜纤维化和血管生成[2]。长期使用高糖透析液可诱导腹膜间皮细胞上皮-间质转化(EMT)，导致腹膜纤维化(PF)的发生[3]。AGEs(晚期糖基化终末产物)来自PD(腹膜透析)溶液中的葡萄糖和GDPs（葡萄糖降解产物），与AGEs受体(RAGE)结合，然后刺激NF-kB，MCP-1和促炎细胞因子，如IL-6和TNF-α上调[4]。RAGE激活介导TGF-β-Smad信号的激活，这是参与腹膜纤维化的重要信号通路[5]。IL-6还可诱导MCP-3和IL-8的形成，它们参与了腹膜炎症的发病机制[6]。NLRP3炎症小体在腹膜炎期间被激活，NLRP3基因敲除和IL-1β受体拮抗剂anakinra可以治疗急性腹膜炎期间的腹膜形态学改变和转运缺陷，这为PD患者腹膜炎的治疗开辟了新的前景[7]。
1.2肾素-血管紧张素-醛固酮系统 每个器官都受到RAAS激活以及由此产生的高血压、细胞增殖、炎症和纤维化的影响[8]。RAAS激活能促使腹膜纤维化的发生[9, 10]。局部RAAS的激活导致转化生长因子-β的产生，从而促进MCs的EMT，增加血管内皮生长因子的产生，所有这些因素都有助于细胞外基质积累和新血管生成，导致PM（腹膜）的发生纤维化[11]。高葡萄糖浓度导致HPMC（腹膜间皮细胞）中RAS激活，RAS阻滞剂改善TGF-β和纤维连接蛋白的产生，保存超滤，并减少腹膜纤维化[12]。HPMCs 在含糖量丰富的环境中，ＲAS 系统被激活，血管紧张素 II 受体的激活导致细胞内 NF-κB 通路的激活，进而导致促纤维化和炎性介质的产生[13]。肾素-血管紧张素-醛固酮系统作为始动因素可进一步诱导腹膜纤维化的进展，但因其下游机制较复杂，还待研究证实。
1.3 TGF-β TGF-β的激活是纤维化的早期重要机制[14],在各种分子机制中，TGF-β在组织纤维化中起核心作用[15]，其中TGF-β1致器官纤维化作用最强; TGF-β1可诱导人腹膜间皮细胞的上皮( epithelialmesenchymal transition，EMT)[16] 。通过特异肽阻断转化生长因子-β信号转导，在啮齿动物模型中减少了纤维化，新生血管生成和EMT，并改善了腹膜功能[17]。腹膜炎时白介素-β( interleukin-β，IL-β) 和肿瘤坏死因子表达可加重TGF-β1慢性诱导作用，并通过增加间质内平滑肌抗体阳性的成纤维细胞的表达促进腹膜纤维化[6]。研究表明：组蛋白是TGF-β1基因启动子，其乙酰化激活TGF-β1/Smad3，促使腹膜间皮细胞EMT，相反C646（H3组蛋白乙酰转移酶抑制剂）逆转EMT、抑制腹膜纤维化[18]。然而，直接阻断转化生长因子-β1的药物在PD的临床实践中不容易使用，因为转化生长因子-β1在调节免疫和炎症反应的功能中起着重要作用[17]。Smad7是一种由 Smad3依赖机制诱导产生的Smad 抑制剂，Smad7可以通过与Ｒ-Smads竞争TβＲ阻断TGF-β受体或通过负反馈机制引起 TGF-β受体降解来抑制Smad2 /3 磷酸化，在鼠腹膜纤维化的模型中，已经证明 Smad7的表达增加可以减弱透析引起的腹膜纤维化、血管生成和炎症，这是通过Smad7抑制腹膜细胞Smad2 /3的活化和TGF-β、纤溶酶原激活物抑制因子-1( plasminogen activator inhibitor-1，PAI-1) 和细胞外基质蛋白的表达实现的[19]。
1.4血管内皮生长因子(VEGF)和CTGF异常表达 在小鼠PD模型中，抑制VEGF的合成减少了腹膜的血管生成和淋巴管生成[20]。转化生长因子-VEGF1-β-A途径可能参与了纤维化相关的腹膜新生血管生成[21]。CTGF被认为是纤维化组织重塑的重要决定因素[22]，CTGF也参与PD相关的腹膜纤维化[21]，CTGF的抑制通过抑制成纤维细胞积聚、新生血管生成和炎症来改善CG（葡萄糖酸氯己定）诱导的腹膜纤维化[23, 24]。CTGF主要在人纤维化腹膜的间皮细胞和成纤维细胞样细胞中被UFF（超滤失败）增强[25]。在CG诱导的大鼠腹膜纤维化模型中，淋巴管标志物和VEGF-C的表达增加，并伴有腹膜炎症和纤维化[26]。CTGF在纤维化的腹膜组织中表达显著增加，其引起纤维化的途径可能与TGF-β相关，且CTGF常作为TGF-β的下游因子，调节间充质细胞向纤维细胞的转化[27]。
1.5 EMT EMT过程包括生理性（即器官发生、发育、伤口愈合和再生）和病理性（即纤维化、肿瘤进展和转移）过程[28]。2型EMT常与炎症、伤口愈合、组织再生和器官纤维化有关[29-32]。慢性EMT2对持续的炎症有反应，最终使器官结构和功能发生破坏，在慢性疾病中，炎症细胞因子和有害信号是恒定的，这意味着只要损伤存在，上皮细胞就会继续向产生胶原的肌成纤维细胞转变[29]。在众多参与腹膜EMT过程的细胞因子中，TGF-β1是中心环节，其中TGF-β／Smad信号转导通路最为重要[17]，EMT在早期是个可逆过程，部分细胞在促生长因子如HGF作用下能重新变回上皮细胞，但发生EMT的细胞可能更易凋亡[33]。
1.6 Wnt/β-catenin Wnt信号在腹膜血管生成中有着重要作用[34]，Wnt/β-catenin表达的增加也有助于腹膜透析诱导的间皮-间质转化和腹膜纤维化[35]。有学者通过观察高糖对腹膜间皮细胞的作用，检测发现随着浓度和作用时间的不断延长，腹膜间皮细胞β—catenin表达明显增加，提示其参与了腹膜透析相关腹膜纤维化的发生[36]。腹膜β-catenin的调节可能是预防PF的一种新的手段[37]。HG诱导57bl/6小鼠腹膜纤维化是通过GSK-3β的磷酸化，增加β-catenin的表达、活化和核转位，改变下游转录因子水平。因此β-catenin通路可能参与促进HG诱导的腹膜纤维化进展过程中的EMT[38]。
1.7激酶 Rho激酶近年才进入人们视野，研究发现它在平滑肌细胞迁移与增殖过程起重要作用，通过Rho/ROCK信号通路激活TGF-β1，其阻断剂能减少腹膜纤维化及血管形成，Rho激酶有望成为治疗新靶点[39]。法舒地尔属于 Rho激酶抑制剂，法舒地尔通过降低腹膜厚度，减少细胞外基质的积累，抑制内脏腹膜tgf-β、fn和α-sma的表达，明显改善腹膜功能，减轻腹膜纤维化[40]。
1.8糖酵解产物 传统的基于葡萄糖的腹膜透析溶液是廉价、安全和有效的渗透液清除溶液，但是高葡萄糖 (HG) 浓度、葡萄糖降解产物和酸度可能有害。腹膜长期暴露于生物不相容的透析液中，以及腹膜炎或腹腔积血反复发作可能导致腹膜损伤，进而导致PF[41]。高糖可使补体系统激活，单核细胞趋蛋白1、TGF-β 等炎性介质上调，并通过各种途径使细胞外基质聚集、肾素-血管紧张素-醛固酮系统表达增加[42]。
1.9蛋白 热休克蛋白47（HSP47）是胶原蛋白合成和分泌的必需的分子伴侣，参与腹膜纤维化形成，利用阳离子明胶微球装载的热休克蛋白47-小干扰RNA则能使HSP47表达沉默，抑制胶原蛋白表达和巨噬细胞渗出，有望用于治疗成为腹膜纤维化[43]。热激蛋白是机体暴露于不良环境时产生的蛋白，研究表明热激蛋白70能调节Smad表达，并抑制EMT的进程，主要通过抑制Smad3、Smad4激活和活性氧类产生，进而阻止腹膜间皮细胞发生EMT，因此热激蛋白70有望成为治疗腹膜纤维化的新型靶点[44]。骨膜蛋白是一种主要来源于成纤维细胞的分泌蛋白，与多种细胞外基质蛋白如纤维连接蛋白、tenascin-c和胶原相互作用[45, 46]，在包裹性腹膜硬化症患者中证实PD液体中的骨膜蛋白水平上调，表明骨膜蛋白可能参与PD患者的腹膜纤维化[47]，研究发现骨膜蛋白在TGF-β1诱导的腹膜系膜细胞的EMT中起作用。PA抑制骨膜蛋白功能导致TGF-β1诱导的EMT消失。此外，腹膜内注射PA（骨膜蛋白结合DNA适配体）成功地抑制了PD动物模型的腹膜纤维化[48]。
1.10基因调控 EZH2（zeste同源物2）是促进腹膜纤维化的重要表观遗传调控因子，靶向EZH2可能具有预防和治疗腹膜纤维化的潜力[49]。有研究表明大量与EMT相关的miRNAs，并控制EMT主转录因子的表达，提示也可能在腹膜纤维化中起作用[50, 51]。实验发现miR-122和miR-30b等促进腹膜纤维化，其中miR-30b直接结合BMP7的3'端非编码区来抑制其表达、促进腹膜纤维化[52]。
1.11 MMP 基质金属蛋白酶（MMP及基质金属蛋白酶抑制剂（TIMP）是数量庞大的细胞因子家族[53] 。MMPs/TIMPs 比值与肿瘤转移、增生性瘢痕形成、器官或组织的纤维化、伤口愈合等生理或病理过程密切相关[54] 。
1.12 GSK3β(糖原合成酶激酶一3β磷酸化) 体内和体外研究发现:GSK3β在成纤维细胞分化和肾纤维化中起重要作[55]，GSK-3β能有效保护健康心脏免受纤维化，损伤导致其抑制，从而激活促纤维化基因程序[56]。他莫昔芬通过抑制GSK-3β、β-catenin的活化，显著减弱腹膜上皮纤维化过程中的EMT[38]。
防治腹膜纤维化的研究进展
2.1药物
2.1.1他汀类药物 Zhang等[57][发现氟伐他汀和SGK1 抑制剂通过抑制SGK信号通路，减轻腹膜纤维化，阿托伐他汀通过减少TGF-β表达，恢复腹膜结构。有研究表明肾素血管紧张素转化酶抑制剂管或者紧张素受体阻滞剂能通过降低纤溶酶原激活物抑制剂（PAI）-1的腹膜浓度起到抑制腹膜纤维的作用[58]，同时其也能减少纤维连接蛋白、TGF-b1和VEGF的表达从而减少腹膜透析患者发生腹膜纤维[59]。大鼠模型腹膜炎时，Ang Ⅱ、TGF-β、纤维蛋白原水平提高，ECM 成分合成增加，而使用厄贝沙坦和醛固酮后能有效抑制腹膜纤维化[60]。
2.1.2醛固酮导致腹膜纤维化的机制之一: 醛固酮水平活跃的间皮细胞常伴有大量巨噬细胞浸润，而增多的巨噬细胞可通过炎性因子导致间皮损伤，从而促使纤维化发生[61]。螺内酯可以减少机械刮削引起的细菌性腹膜炎和腹膜纤维化动物模型中的腹膜增厚和炎症[60, 62]，螺内酯减少腹膜炎症和纤维化，这与腹腔巨噬细胞分泌减少，c-Jun氨基末端激酶(JNK)途径失活以及随后TGF-b1表达下调有关[62]。
2.1.3维生素D抑制促纤维化因子、TGF及其信号通路抑制EMT，在形态及功能方面缓解腹膜退化，保持腹膜完整，维生素D受体活化剂下调炎症及纤维化相关体液因子及抗血管因子生成，上调CD4+和CD8+调节T细胞，减少IL-17表达，减轻腹膜重塑及纤维化，其药理作用呈剂量依赖性[63]。1，25-二羟基维生素D3(1，25[OH]2D3)通过抑制组蛋白去乙酰化酶3(HDAC3)的表达而逆转人腹膜间皮细胞的上皮-间质转化(EMT)过程。同时通过调节Wnt/b-catenin信号通路增加维生素D受体(VDR)的表达[64]。
2.1.4中药方面 姜黄素治疗可显著增加PD大鼠的UFV（超滤体积），降低MTG（葡萄糖质量转移）和腹膜厚度，姜黄素可明显降低PD大鼠腹腔液中升高的转化生长因子-β1。姜黄素可降低PD大鼠腹膜TAK1、JNK和p38的mRNA表达以及p-TAK1、p-JNK和p-p38的蛋白表达，姜黄素可能是预防和治疗腹膜纤维化的潜在药物[65]。姚素花等[66]予新加入 PD 患者口服百令胶囊，并分别于入选时及 PD 治疗 1、3、6个月检测腹膜透析液中TGF-β1、血管内皮生长因子(VEGF)的水平，结果发现: PD患者随透析时间延长，腹膜透析液中TGF-β1、VEGF水平不断升高，而百令胶囊组则无明显变化，研究表明百令胶囊可以降低PD患者腹透液中上诉因子水平，可能起到抑制腹膜纤维化的发生。黄琳等[67]将 82 例 CAPD 患者随机分为对照组和研究组各 41 例，研究组采用尿毒康合剂( 组成 : 黄芪50 g，茯苓 15 g，白术 15 g，大黄 10 g，川芎 10 g，红花 10 g，丹参 15 g，地榆 15 g) 口服 3 个月，观察对腹膜透析患者的透析效能及腹膜纤维化的影响。结果显示，尿毒康合剂能明显减少腹透液中纤维连接蛋白( fibronectin，FN) 、TGF-β1 及血清HMGB-1、hs-CＲP、IL-6 值( P ＜ 0.05),表明尿毒康合剂可以抑制腹膜纤维化和微炎症。扶肾颗粒中黄芪为君药，淫羊藿、半夏、陈皮共为臣药，丹参、熟大黄、鬼箭羽三者并列佐使药，扶肾颗粒在抑制腹膜纤维化的同时，还能通过下调乙二醛酶－1( glyoxalase-1，Glo-1) 的表达来减少血清终末期糖基化产物的蓄积，保护残肾功能，进而延缓腹膜超滤衰竭[68]。淫羊藿苷具有强效的抗炎，抗氧化剂和免疫抑制的药理特性，在抗纤维化[69, 70]、肿瘤[71]、自体免疫和炎性疾病方面可见有效的治疗效果[72]。淫羊藿苷的抗炎作用，其直接抑制LPS刺激的NO释放、Ca2+内流、磷酸化p38、磷酸化JNK和炎性细胞因子的产生，对酵母多糖诱导的腹膜炎的保护作用也提供了其体内抗炎活性的证据，淫羊藿苷预处理减少酵母多糖诱导的急性腹膜炎中这些炎症介质的过量产生[73]。
2.2.其他方面
2.2.1 免疫调节 RABY 等[74]]发现采用TLR 抑制剂可溶性TLR 2 或敲除TLR 2/4 基因等措施均可抑制促炎因子和促纤维化因子的释放，这表明TLR-DAMPs 或为治疗PF 的潜在靶点。TAK242（TLR4抑制剂）治疗对预防纤维化非常有效，并发现纤维化腹膜内膜厚度减少>60%，纤维化和炎症基因(Col1a1和IL6)表达减弱[75]。RAPA（雷帕霉素）和BEZ235（新型PI3K/mTOR双阻滞剂）都显著下调mTOR途径以抑制腹膜纤维化的发展和进展[76]。WAKABAYASHI等[77]发现予大鼠口服抗氧化剂虾青素能抑制PF的发展，甚至可预防腹膜损伤，其机制是虾青素通过抑制炎症和氧化过程从而发挥抗血管生成及降低腹膜TGF-β1、Snail mRNA 和α-MA 的表达的作用。
2.2.2 改变传统腹透液成分 乳酸盐和碳酸氢盐/乳酸盐缓冲溶液（BLS）与传统腹膜透析液相比能维持间皮细胞完整性和功能的能力，每天暴露于BLS液中阻止了αSMA和胶原I的积累。表明使用低GDPs溶液在体外与较少的αSMA表达相关，并且在大鼠的腹膜中较少发生纤维化反应[78]。KIHM等[79]在尿毒症大鼠PD模型中，用苯磷硫胺处理后，大鼠肾脏和腹膜AGE 及RAGE 的表达减少，肾小球和肾小管间质损伤降低，腹膜功能有明显的改善，这提示该药物具有保护尿毒症大鼠PD和残肾及腹膜功能的作用。
综上所述，腹膜纤维化的发生机制与肾素-血管紧张素-醛固酮系统、TGF-β1因子、GSK-3β因子，VEGF及 CTGF 异常表达、EMT、Wnt信号通路、激酶、糖酵解产物、基因调控等有着密切关系，抗纤维化药物的研发是解决这一临床难点的关键之一。
期刊文章分类查询,尽在期刊图书馆
References
[1] Plum J, Hermann S, Fussh?ller A, et al. Peritoneal sclerosis in peritoneal dialysis patients related to dialysis settings and peritoneal transport properties. Kidney Int Suppl. 2001. 78: S42-7.
[2] Zhang Z, Jiang N, Ni Z. Strategies for preventing peritoneal fibrosis in peritoneal dialysis patients: new insights based on peritoneal inflammation and angiogenesis. Front Med. 2017. 11(3): 349-358.
[3] Zhou Q, Bajo MA, Del Peso G, Yu X, Selgas R. Preventing peritoneal membrane fibrosis in peritoneal dialysis patients. Kidney Int. 2016. 90(3): 515-24.
[4] Boulanger E, Wautier MP, Wautier JL, et al. AGEs bind to mesothelial cells via RAGE and stimulate VCAM-1 expression. Kidney Int. 2002. 61(1): 148-56.
[5] De Vriese AS. The John F. Maher Recipient Lecture 2004: Rage in the peritoneum. Perit Dial Int. 2005. 25(1): 8-11.
[6] Feurino LW, Zhang Y, Bharadwaj U, et al. IL-6 stimulates Th2 type cytokine secretion and upregulates VEGF and NRP-1 expression in pancreatic cancer cells. Cancer Biol Ther. 2007. 6(7): 1096-100.
[7] Hautem N, Morelle J, Sow A, et al. The NLRP3 Inflammasome Has a Critical Role in Peritoneal Dialysis-Related Peritonitis. J Am Soc Nephrol. 2017. 28(7): 2038-2052.
[8] Patel S, Rauf A, Khan H, Abu-Izneid T. Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies. Biomed Pharmacother. 2017. 94: 317-325.
[9] Bozkurt D, Cetin P, Sipahi S, et al. The effects of renin-angiotensin system inhibition on regression of encapsulating peritoneal sclerosis. Perit Dial Int. 2008. 28 Suppl 5: S38-42.
[10] Nakamoto H, Imai H, Fukushima R, Ishida Y, Yamanouchi Y, Suzuki H. Role of the renin-angiotensin system in the pathogenesis of peritoneal fibrosis. Perit Dial Int. 2008. 28 Suppl 3: S83-7.
[11] Bajo MA, Del Peso G, Teitelbaum I. Peritoneal Membrane Preservation. Semin Nephrol. 2017. 37(1): 77-92.
[12] Noh H, Ha H, Yu MR, Kim YO, Kim JH, Lee HB. Angiotensin II mediates high glucose-induced TGF-beta1 and fibronectin upregulation in HPMC through reactive oxygen species. Perit Dial Int. 2005. 25(1): 38-47.
[13] Morinelli TA, Luttrell LM, Strungs EG, Ullian ME. Angiotensin II receptors and peritoneal dialysis-induced peritoneal fibrosis. Int J Biochem Cell Biol. 2016. 77(Pt B): 240-50.
[14] Garosi G, Cappelletti F, Di Paolo N. Fibrosis and sclerosis: different disorders or different stages. Contrib Nephrol. 2006. 150: 62-69.
[15] Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis. Nat Rev Nephrol. 2016. 12(6): 325-38.
[16] Margetts PJ, Bonniaud P, Liu L, et al. Transient overexpression of TGF-{beta}1 induces epithelial mesenchymal transition in the rodent peritoneum. J Am Soc Nephrol. 2005. 16(2): 425-36.
[17] Loureiro J, Aguilera A, Selgas R, et al. Blocking TGF-β1 protects the peritoneal membrane from dialysate-induced damage. J Am Soc Nephrol. 2011. 22(9): 1682-95.
[18] Yang Y, Liu K, Liang Y, Chen Y, Chen Y, Gong Y. Histone acetyltransferase inhibitor C646 reverses epithelial to mesenchymal transition of human peritoneal mesothelial cells via blocking TGF-β1/Smad3 signaling pathway in vitro. Int J Clin Exp Pathol. 2015. 8(3): 2746-54.
[19] Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-β signaling in fibrosis. Growth Factors. 2011. 29(5): 196-202.
[20] González-Mateo GT, Aguirre AR, Loureiro J, et al. Rapamycin Protects from Type-I Peritoneal Membrane Failure Inhibiting the Angiogenesis, Lymphangiogenesis, and Endo-MT. Biomed Res Int. 2015. 2015: 989560.
[21] Kinashi H, Ito Y, Sun T, Katsuno T, Takei Y. Roles of the TGF-β?VEGF-C Pathway in Fibrosis-Related Lymphangiogenesis. Int J Mol Sci. 2018. 19(9).
[22] Perbal B. CCN proteins: multifunctional signalling regulators. Lancet. 2004. 363(9402): 62-4.
[23] Sakai N, Nakamura M, Lipson KE, et al. Inhibition of CTGF ameliorates peritoneal fibrosis through suppression of fibroblast and myofibroblast accumulation and angiogenesis. Sci Rep. 2017. 7(1): 5392.
[24] Toda N, Mori K, Kasahara M, et al. Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation. Nephrol Dial Transplant. 2018. 33(6): 943-953.
[25] Mizutani M, Ito Y, Mizuno M, et al. Connective tissue growth factor (CTGF/CCN2) is increased in peritoneal dialysis patients with high peritoneal solute transport rate. Am J Physiol Renal Physiol. 2010. 298(3): F721-33.
[26] Kinashi H, Ito Y, Mizuno M, et al. TGF-β1 promotes lymphangiogenesis during peritoneal fibrosis. J Am Soc Nephrol. 2013. 24(10): 1627-42.
[27] Liu FY, Xiao L, Peng YM, et al. Inhibition effect of small interfering RNA of connective tissue growth factor on the expression of vascular endothelial growth factor and connective tissue growth factor in cultured human peritoneal mesothelial cells. Chin Med J (Engl). 2007. 120(3): 231-6.
[28] Kang SH, Kim SW, Kim KJ, et al. Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells. Kidney Res Clin Pract. 2019 .
[29] Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009. 119(6): 1420-8.
[30] Lee K, Nelson CM. New insights into the regulation of epithelial-mesenchymal transition and tissue fibrosis. Int Rev Cell Mol Biol. 2012. 294: 171-221.
[31] López-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009. 1(6-7): 303-14.
[32] Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008. 214(2): 199-210.
[33] Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009. 139(5): 871-90.
[34] Padwal M, Cheng G, Liu L, et al. WNT signaling is required for peritoneal membrane angiogenesis. Am J Physiol Renal Physiol. 2018. 314(6): F1036-F1045.
[35] Guo Y, Sun L, Xiao L, et al. Aberrant Wnt/Beta-Catenin Pathway Activation in Dialysate-Induced Peritoneal Fibrosis. Front Pharmacol. 2017. 8: 774.
[36] Tao H, Yang JJ, Shi KH, Li J. Wnt signaling pathway in cardiac fibrosis: New insights and directions. Metabolism. 2016. 65(2): 30-40.
[37] Yu M, Shi J, Sheng M, et al. Astragalus Inhibits Epithelial-to-Mesenchymal Transition of Peritoneal Mesothelial Cells by Down-Regulating β-Catenin. Cell Physiol Biochem. 2018. 51(6): 2794-2813.
[38] Yan P, Tang H, Chen X, et al. Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK-3β/β-catenin axis activation. Biosci Rep. 2018. 38(6).
[39] Peng W, Zhou Q, Ao X, Tang R, Xiao Z. Inhibition of Rho-kinase alleviates peritoneal fibrosis and angiogenesis in a rat model of peritoneal dialysis. Ren Fail. 2013. 35(7): 958-66.
[40] Wang Q, Yang X, Xu Y, et al. RhoA/Rho-kinase triggers epithelial-mesenchymal transition in mesothelial cells and contributes to the pathogenesis of dialysis-related peritoneal fibrosis. Oncotarget. 2018. 9(18): 14397-14412.
[41] Bansal N, Katz R, Seliger S, et al. Galectin-3 and Soluble ST2 and Kidney Function Decline in Older Adults: The Cardiovascular Health Study (CHS). Am J Kidney Dis. 2016. 67(6): 994-6.
[42] Hattori T, Matsubara A, Taniguchi K, Ogura Y. Aldose reductase inhibitor fidarestat attenuates leukocyte-endothelial interactions in experimental diabetic rat retina in vivo. Curr Eye Res. 2010. 35(2): 146-54.
[43] Obata Y, Nishino T, Kushibiki T, et al. HSP47 siRNA conjugated with cationized gelatin microspheres suppresses peritoneal fibrosis in mice. Acta Biomater. 2012. 8(7): 2688-96.
[44] Liu J, Bao J, Hao J, Peng Y, Hong F. HSP70 inhibits high glucose-induced Smad3 activation and attenuates epithelial-to-mesenchymal transition of peritoneal mesothelial cells. Mol Med Rep. 2014. 10(2): 1089-95.
[45] Kii I, Ito H. Periostin and its interacting proteins in the construction of extracellular architectures. Cell Mol Life Sci. 2017. 74(23): 4269-4277.
[46] Kudo A, Kii I. Periostin function in communication with extracellular matrices. J Cell Commun Signal. 2018. 12(1): 301-308.
[47] Braun N, Sen K, Alscher MD, et al. Periostin: a matricellular protein involved in peritoneal injury during peritoneal dialysis. Perit Dial Int. 2013. 33(5): 515-28.
[48] Nam BY, Park JT, Kwon YE, et al. Periostin-Binding DNA Aptamer Treatment Ameliorates Peritoneal Dialysis-Induced Peritoneal Fibrosis. Mol Ther Nucleic Acids. 2017. 7: 396-407.
[49] Shi Y, Tao M, Wang Y, et al. Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis. J Pathol. 2019 .
[50] Zhang J, Zhang H, Liu J, et al. miR-30 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in hepatocyte by targeting Snail1. Biochem Biophys Res Commun. 2012. 417(3): 1100-5.
[51] Cicchini C, de Nonno V, Battistelli C, et al. Epigenetic control of EMT/MET dynamics: HNF4α impacts DNMT3s through miRs-29. Biochim Biophys Acta. 2015. 1849(8): 919-29.
[52] Lin F, Wu X, Zhang H, et al. A microrna screen to identify regulators of peritoneal fibrosis in a rat model of peritoneal dialysis. BMC Nephrol. 2015. 16: 48.
[53] Franco C, Patricia HR, Timo S, Claudia B, Marcela H. Matrix Metalloproteinases as Regulators of Periodontal Inflammation. Int J Mol Sci. 2017. 18(2).
[54] Lindberg RL, De Groot CJ, Montagne L, et al. The expression profile of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lesions and normal appearing white matter of multiple sclerosis. Brain. 2001. 124(Pt 9): 1743-53.
[55] Singh SP, Tao S, Fields TA, Webb S, Harris RC, Rao R. Glycogen synthase kinase-3 inhibition attenuates fibroblast activation and development of fibrosis following renal ischemia-reperfusion in mice. Dis Model Mech. 2015. 8(8): 931-40.
[56] Guo Y, Gupte M, Umbarkar P, et al. Entanglement of GSK-3β, β-catenin and TGF-β1 signaling network to regulate myocardial fibrosis. J Mol Cell Cardiol. 2017. 110: 109-120.
[57] Zhang L, Liu J, Liu Y, et al. Fluvastatin inhibits the expression of fibronectin in human peritoneal mesothelial cells induced by high-glucose peritoneal dialysis solution via SGK1 pathway. Clin Exp Nephrol. 2015. 19(3): 336-42.
[58] Tro?t Rupnik A, Pajek J, Gu?ek A, et al. Influence of renin-angiotensin-aldosterone system-blocking drugs on peritoneal membrane in peritoneal dialysis patients. Ther Apher Dial. 2013. 17(4): 425-30.
[59] Jing S, Kezhou Y, Hong Z, Qun W, Rong W. Effect of renin-angiotensin system inhibitors on prevention of peritoneal fibrosis in peritoneal dialysis patients. Nephrology (Carlton). 2010. 15(1): 27-32.
[60] Ersoy R, Celik A, Yilmaz O, et al. The effects of irbesartan and spironolactone in prevention of peritoneal fibrosis in rats. Perit Dial Int. 2007. 27(4): 424-31.
[61] Vernon MA, Mylonas KJ, Hughes J. Macrophages and renal fibrosis. Semin Nephrol. 2010. 30(3): 302-17.
[62] Zhang L, Hao JB, Ren LS, Ding JL, Hao LR. The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis. Lab Invest. 2014. 94(8): 839-50.
[63] Lee YC, Hung SY, Liou HH, et al. Vitamin D can ameliorate chlorhexidine gluconate-induced peritoneal fibrosis and functional deterioration through the inhibition of epithelial-to-mesenchymal transition of mesothelial cells. Biomed Res Int. 2015. 2015: 595030.
[64] Liu KH, Fu J, Zhou N, et al. 1,25-Dihydroxyvitamin D3 Prevents Epithelial-Mesenchymal Transition of HMrSV5 Human Peritoneal Mesothelial Cells by Inhibiting Histone Deacetylase 3 (HDAC3) and Increasing Vitamin D Receptor (VDR) Expression Through the Wnt/β-Catenin Signaling Pathway. Med Sci Monit. 2019. 25: 5892-5902.
[65] Zhao JL, Zhang T, Shao X, Zhu JJ, Guo MZ. Curcumin ameliorates peritoneal fibrosis via inhibition of transforming growth factor-activated kinase 1 (TAK1) pathway in a rat model of peritoneal dialysis. BMC Complement Altern Med. 2019. 19(1): 280.
[66] 姚素花, 麦李明, 石俊婷. 百令胶囊对腹透患者腹透液中TGF-β1、VEGF水平的影响. 中成药. 2017. 39(09): 1980-1982.
[67] 黄琳, 李燕林, 庞捷, 李锦山. 尿毒康合剂对腹膜透析患者腹膜透析效能及腹膜纤维化影响的临床观察. 辽宁中医杂志. 2017. 44(10): 2097-2100.
[68] 唐阁, 杨洪涛, 林燕, 郭淑婷, 布亚男, 梅霞. 扶肾颗粒改善腹膜超滤功能的分子机制. 中国实验方剂学杂志. 2017. 23(23): 103-108.
[69] Chen HA, Chen CM, Guan SS, Chiang CK, Wu CT, Liu SH. The antifibrotic and anti-inflammatory effects of icariin on the kidney in a unilateral ureteral obstruction mouse model. Phytomedicine. 2019. 59: 152917.
[70] Algandaby MM, Breikaa RM, Eid BG, Neamatallah TA, Abdel-Naim AB, Ashour OM. Icariin protects against thioacetamide-induced liver fibrosis in rats: Implication of anti-angiogenic and anti-autophagic properties. Pharmacol Rep. 2017. 69(4): 616-624.
[71] Hao H, Zhang Q, Zhu H, et al. Icaritin promotes tumor T-cell infiltration and induces antitumor immunity in mice. Eur J Immunol. 2019 .
[72] 路宇仁, 陈昳冰, 崔元璐, 王强松. 淫羊藿苷药理作用研究进展. 中国实验方剂学杂志. 2018. 24(17): 209-220.
[73] Lai X, Ye Y, Sun C, et al. Icaritin exhibits anti-inflammatory effects in the mouse peritoneal macrophages and peritonitis model. Int Immunopharmacol. 2013. 16(1): 41-9.
[74] Raby AC, González-Mateo GT, Williams A, et al. Targeting Toll-like receptors with soluble Toll-like receptor 2 prevents peritoneal dialysis solution-induced fibrosis. Kidney Int. 2018. 94(2): 346-362.
[75] Bhattacharyya S, Wang W, Tamaki Z, et al. Pharmacological Inhibition of Toll-Like Receptor-4 Signaling by TAK242 Prevents and Induces Regression of Experimental Organ Fibrosis. Front Immunol. 2018. 9: 2434.
[76] Xu T, Lin T, Xie J, Ren H, Chen N, Wang W. Comparison of anti-peritoneal fibrotic effects between an mTORC1-specific blocker and a PI3K/mTOR dual-blocker. Ren Fail. 2019. 41(1): 267-277.
[77] Wakabayashi K, Hamada C, Kanda R, et al. Oral Astaxanthin Supplementation Prevents Peritoneal Fibrosis in Rats. Perit Dial Int. 2015. 35(5): 506-16.
[78] Vila Cuenca M, Keuning ED, Talhout W, et al. Differences in peritoneal response after exposure to low-GDP bicarbonate/lactate-buffered dialysis solution compared to conventional dialysis solution in a uremic mouse model. Int Urol Nephrol. 2018. 50(6): 1151-1161.
[79] Kihm LP, Müller-Krebs S, Klein J, et al. Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis. J Am Soc Nephrol. 2011. 22(5): 914-26
论文作者:李林煜
论文发表刊物:《医师在线》2020年5期
论文发表时间:2020/4/10
标签：腹膜论文; 细胞论文; 抑制论文; 炎症论文; 蛋白论文; 血管论文; 诱导论文; 《医师在线》2020年5期论文;