FGF-23/Klotho轴与慢性肾脏病的研究进展*
·综述·
FGF-23/Klotho轴与慢性肾脏病的研究进展*
朱万胜1 综述 吴道全1、2 杨舸2 审校
(1，西南医科大学，四川 泸州 646000；2.内江市第二人民医院肾内科，四川 内江 641100)
【摘要】成纤维细胞生长因子-23(Fibroblast growth factor-23,FGF-23)是一种调节磷和活性维生素D(1,25(OH)2D)代谢的一种骨源性激素。FGF-23在其共受体Klotho的协同下与成纤维细胞生长因子受体-1(Fibroblast growth factor receptor-1,FGFR-1)结合，通过提高肾脏对磷的排泄，维持血清磷水平在正常范围内。此外，FGF-23还能减少1,25(OH)2D的合成和促进其降解，从而减少肠道对磷的吸收。而且，FGF-23还可作用于甲状旁腺，减少甲状旁腺激素(PTH)的合成及其分泌。在慢性肾脏病(CKD)的发展进程中,在血清磷浓度升高发生的很早之前，随着肾功能降低，血清FGF-23水平就明显升高，而血清Klotho却显著降低。目前研究表明FGF-23/Klotho轴与CKD病程中的钙磷代谢紊乱、继发性甲状旁腺功能亢进症(Secondary hyperparathyroidism,SHPT)和心血管疾病(Cardiovascular diseases,CVD)等并发症密切相关，在慢性肾脏病-矿物质及骨代谢异常(CKD-MBD)的发生发展中起重要作用。近年来，对FGF-23/Klotho轴与CKD关系不断的深入研究，为CKD-MBD的诊断和治疗带来了新的视角。本文旨在就FGF-23/Klotho轴与CKD的研究进展作一综述。
【关键词】成纤维细胞生长因子-23；Klotho；慢性肾脏病；继发性甲状旁腺功能亢进症
慢性肾脏病(Chronic kidney disease,CKD)发病率日益上升，且预后较差，如何早期诊断和处理好CKD患者的各种并发症已经成为影响其生命和生活质量的重要因素，慢性肾脏病-矿物质和骨代谢异常(Chronic kidney disease-mineral and bone metabolism disorder,CKD-MBD)即为其中之一[1]。CKD-MBD包括以下三种异常：①钙、磷、甲状旁腺激素(Parathyroid hormone,PTH)和维生素D(VitD)代谢异常。②骨转运、骨矿化、骨容量和骨的生长异常。③血管和软组织钙化[2]，上述三方面的异常无不与CKD患者的预后密切相关，严重影响CKD患者的生存质量。目前已有研究表明，FGF-23/Klotho轴在CKD-MBD的病理生理机制中起了重要作用。近年来，随着研究的不断深入，这一领域向我们展示了更加丰富的视野，为CKD及其SHPT、CVD等并发症的早期诊断和治疗带来了许多新启示，本文就FGF-23/Klotho轴与CKD的研究进展作如下综述。
1 FGF-23和Klotho的生物学特性
FGF-23属于内分泌性成纤维细胞生长因子家族中的一员[3]，其基因定位于12号染色体，是一种由251个氨基酸组成，分子量32kDa的蛋白，它主要由骨细胞和成骨细胞合成分泌[4-5]，其mRNA也在其他组织中表达，包括肝脏、心肌、甲状旁腺。研究表明，FGF-23与常染色体显性遗传性低磷血症佝偻病、X-连锁低磷性佝偻病、肿瘤性骨软化症均有关[6]。动物实验研究发现，FGF-23基因缺陷小鼠表现为高钙血症、高磷血症、异位钙化、严重骨质疏松[7]；相反，FGF-23过表达小鼠则表现出低磷血症、佝偻病、骨软化等[8]。上述研究表明FGF-23可能与钙磷代谢密切相关，在多种矿物质骨疾病的发病中起重要作用。
Klotho是Kuro-o等发现的抑制衰老相关的基因，并以纺织生命之线的希腊女神—Klotho命名[9]。该基因主要在肾远曲小管、甲状旁腺、脉络丛中表达，最近发现其在血管、巨噬细胞中也有表达[9-11]，其编码的蛋白也命名为Klotho，分为膜型和分泌型，其中分泌型Klotho(sKlotho)可在血液、尿液、脑脊液中检测到[12-13]。研究表明Klotho具有广泛而重要的生物学作用，膜型klotho(mKlotho)可作为FGF-23必需的受体辅助因子参与磷的调节，而sKlotho则能独立发挥多项作用，如通过抑制Wnt和胰岛素/胰岛素样生长因子-1(IGF-1)路径信号途径及抗氧化应激、抗炎、抗纤维化而发挥抗衰老和组织保护作用[14-17]；通过抑制血管钙化和刺激内皮细胞中一氧化氮的合成而保护血管[18]等。
动物研究发现，FGF-23基因缺陷小鼠和Klotho基因突变小鼠表现出相似的表型，包括寿命缩短、性腺功能减退、骨密度降低或骨质疏松、异位钙化、高钙血症、高磷血症和VitD水平升高[7,9,14]等，这是否表明二者具有相同的信号通路呢？的确，现已确定mKlotho是FGF-23发挥其生物学活性必需的辅助因子，mKlotho可增强FGF-23与其受体FGFR-1的亲和力，协同FGF-23对磷、VitD和PTH代谢的进行调节[14，19]，并且有学者提出了在骨-肾-甲状旁腺轴中起重要作用的FGF-23/Klotho轴的概念[18]。
2 FGF-23/Klotho轴与钙、磷、VitD和PTH代谢
理想的磷平衡状态对细胞信号传导、能量代谢、骨矿化等许多生理功能都至关重要。生理性磷平衡的维持需要骨、肾、小肠、甲状腺的相互作用。磷在小肠的吸收有赖于钠-磷协同转运体-2b(NaPi-2b)的促进作用，1,25(OH)2D可增加NaPi-2b在小肠的表达，而促进磷的吸收。类似地，磷在肾小管的重吸收主要由钠-磷协同转运体NaPi-2a和NaPi-2c来完成。PTH则可抑制近端小管上NaPi依赖的磷吸收而增加尿磷排泄。新型调磷因子FGF-23、Klotho可与传统的调磷因子PTH和VitD相互作用参与磷的调节。
FGF-23与mKlotho-FGFR-1复合物结合，一方面，可抑制近端小管上NaPi-2a和NaPi-2c的表达，减少肾小管磷的重吸收[20]；另一方面，还可通过抑制1α-羟化酶和刺激24-羟化酶，减少肾脏1,25(OH)2D的产生[14,21]，由此减少肠道对钙、磷的吸收。此外，最近有研究发现，FGF-23还可以在FGFR/sKlotho的协同下，促进远端小管TRPV5对钙的重吸收[22]。有研究显示sKlotho还可直接抑制NaPi-2a在近端小管上表达[23]发挥独立于FGF-23的调磷作用。可见FGF-23及Klotho与钙磷代谢密切相关。1,25(OH)2D与其核受体(VDR)结合可上调骨源性FGF-23的产生[24]。FGF-23的水平也受磷摄入的影响，有动物实验表明，高磷饮食可增加5/6肾切除SD大鼠血清磷和血清FGF-23水平[25]；另一项在三个不同地区人群中进行的横断面研究表明，FGF-23水平与饮食中磷的摄入量和磷排泄分数呈正相关，与血磷无相关性[26]。Klotho和FGFR-1在甲状旁腺均有表达，Klotho和FGF-23对PTH的作用显得更为复杂。FGF-23可通过一种Klotho依赖的机制激活FGFR-1，进而抑制PTH的分泌[27]；FGF-23还可通过上调甲状旁腺组织中活性1,25(OH)2D受体(VDR)的表达，从而抑制PTH的产生，因为活性1,25(OH)2D可与VDR结合，抑制PTH的基因转录[28-29]。然而，研究发现Klotho却可通过调节Na+-K+ ATP酶的活性，以一种独立于FGF-23的方式促进PTH的合成、分泌[27-30]。相反，PTH却可促进FGF-23的产生，研究表明PTH替代治疗对甲状旁腺切除大鼠FGF-23表现为剂量依赖性增加作用[31]，最近也有研究发现，PTH可通过激活孤儿核受体相关因子1(Nurr1),增加骨细胞中FGF-23的转录[32]。上述研究均说明FGF-23及Klotho的表达均会影响PTH的分泌，进而对钙磷代谢产生重要影响。
3 FGF-23/Klotho轴与CKD
3.1 CKD中FGF-23、Klotho的异常表达 FGF-23升高和Klotho下降常常在CKD早中期就开始出现，明显早于血磷和PTH的升高[33-37]。Klotho主要在肾脏表达，作为其主要的来源器官之一[38]，在肾功能不全初期就可能会导致Klotho表达减少，有CKD动物模型和CKD患者肾活检组织研究发现Klotho蛋白和/或Klotho mRNA表达均降低[10,39-41]。在CKD的很早期，随着完整肾单位数量的逐渐减少，FGF-23逐渐升高，这被认为是机体为维持系统性磷平衡而做出的适应性代偿性反应[6,39,42]。升高的FGF-23可通过FGF-23-Klotho信号介导提高尿磷排泄，还可降低1,25(OH)2D水平，从而减少肠道对钙磷的吸收，使血磷维持正常。随着CKD的进展，进一步减少的Klotho不足以支持FGF-23—Klotho信号，所以FGF-23不能代偿肾衰竭相关性磷潴留，高磷血症随即发生，并促进FGF-23分泌进一步增加[39]。研究发现肾移植后患者同时合并高FGF-23和低磷血症，且随着肾移植后的时间推移，FGF-23水平越低，而磷逐渐升高至正常，可支持上述观点[43]。许多研究[33-37]均认为FGF-23升高和Klotho下降可作为CKD的一项早期生物标记物，为CKD进展的有效监测和早期干预治疗带来新的希望。
3.2 FGF-23/Klotho与SHPT 众所周知，SHPT是CKD的主要并发症。传统的观点认为低钙血症、高磷血症和1,25(OH)2D缺乏是SHPT的刺激因素，因为升高的FGF-23降低1,25(OH)2D[39]，导致VitD对PTH基因转录的抑制作用减弱和持续性低钙血症，为了维持系统性钙平衡，钙敏感受体会介导甲状旁腺增生，PTH的产生增加[42,6]。给CKD大鼠注射FGF-23抗体以中和FGF-23，阻止了1,25(OH)2D降低和SHPT进展，血钙升高，支持上述假说[44]。但最近的研究发现尿毒症患者甲状旁腺组织中Klotho和FGFR1表达均下降[45-46]，而PTH的分泌明显升高，这表明由于Klotho和FGFR1 缺乏，导致作用于甲状旁腺的FGF-23—Klotho信号中断, PTH分泌异常升高，可能是SHPT的发展中的重要因素[6]，而升高的PTH又进一步促进骨中FGF-23的产生。
3.3 FGF-23/Klotho与CVD CKD是CVD，包括左心室肥厚(LVH)、血管钙化、高血压等心血管疾病的主要风险，而CVD又是CKD患者主要的死亡原因。近年来，FGF-23/Klotho与CKD患者CVD的关系也日益引起人们的关注。Stevens[47]等，以“金标准”方法CMRI评估CKD患者FGF-23与LVH的关系发现，FGF-23浓度与LVMI(左心室重量指数)呈正相关，FGF-23是CKD患者LVH的独立预测因子。同时，他们以人脐静脉内皮细胞为标本，通过体外实验表明FGF-23对内皮功能紊乱和LVH有直接的促进作用。类似地，Milovanova[34、48]等研究发现在CKD患者中，高FGF-23水平和高LVM(左心室质量)之间有直接相关性，且在高血压患者中最显著，降低的Klotho水平和增厚的左室后壁则表现出很强的负相关性。也有研究[34、48]发现，CKD患者血压升高程度与FGF-23呈正相关，与Klotho呈负相关，这均可促进CKD患者LVH的进展，导致左心功能障碍。Yu J[41]等的动物实验则发现，尿毒症小鼠动脉粥样硬化的发生伴随着Klotho表达的下降。在一项维持性血液透析患者中进行的横断面研究中[49]，sKlotho较对照组明显降低，合并低sKlotho的患者颈动脉内膜中层厚度(CIMT)增加，左心功能障碍和冠状动脉疾病(CAD)发生率增高，通过回归分析表明sKlotho与CIMT、CAD和LVEF(左室射血分数)呈显著独立相关。另一项临床研究也发现[50]，轻中度CKD患者的主动脉钙化程度与FGF-23呈正相关，与Klotho呈负相关。Lim[51]等对人类动脉和主动脉平滑肌细胞进行研究发现，血管细胞也是FGF-23的一种Klotho依赖靶组织，CKD在实质上是一种血管Klotho缺乏的状态，CKD患者高水平的FGF-23不能发挥血管保护作用是由于Klotho/FGFR缺乏介导的抵抗效应。该研究还发现，VDR激活剂治疗能够通过上调血管Klotho的表达，而介导FGF-23的抗血管钙化作用。上述研究结果表明，FGF-23/Klotho与CKD患者CVD的发病密切相关，可能也是CKD患者CVD的一项敏感的预测因子，并且可能成为CKD患者CVD治疗的新靶点。
3.4 FGF-23/Klotho与CKD进展及预后 目前对于FGF-23/Klotho轴，引人关注的还有其作为肾病进展预测指标的作用。许多研究发现，早在CKD2期就检测到FGF-23升高和Klotho降低，远早于磷和PTH的改变，并随着肾功下降不断进展，且血清Klotho水平与肾小球滤过率(Glomerular filtration rate，GFR)呈正比，血清FGF-23浓度与GFR呈反比[33-37]。这些研究结果表明FGF-23/Klotho可能与CKD的进展有关，可以作为CKD早期识别和监测进展的一项新型生物标志物[33-37]。结合前文所述，FGF-23/Klotho轴与CKD预后密切相关的主要并发症，如钙磷代谢紊乱、SHPT和 CVD都有紧密联系。此外，有研究发现FGF-23的升高是CKD患者发展至ESRD和死亡率的独立危险因素[52]，也有研究指出升高的FGF-23也是肾移植患者术后失功和死亡的独立风险因素[53]，同时有研究认为Klotho也有望成为预测CKD预后的一项敏感的早期标记物[54]。
4 小结与展望
目前许多研究表明早在CKD2期开始Klotho和FGF-23就随着GFR降低而出现改变，并且与CKD的SHPT、CVD等并发症密切相关，对CKD早期诊断、并发症预测、预后判断具有重要意义。但也有冲突的研究结论提出[55]，也可能客观存在FGF-23/Klotho检测试剂盒质量不统一、检测方法不足[56-57]等问题，因此FGF-23、Klotho能否作为CKD实用可靠的早期标记物仍值得进一步研究。另一方面，随着对FGF-23/Klotho与CKD相关性的深入研究，也为CKD-MBD的治疗带来了新的启示。例如，对CKD大鼠注射FGF-23抗体，可改善SHPT、提高血清VitD和Ca浓度，但出现了FGF-23抗体剂量依赖性的血磷升高和主动脉瓣钙化[44]，这提示我们今后可研究FGF-23基因消融配合饮食磷限制和/或磷结合剂是否可以改善CKD预后。再如，Lim[51]等研究发现，VDR激活剂治疗可提高血管Klotho的表达，有助于FGF-23抗血管钙化，这也为抗CKD血管钙化的治疗提供了新的思路。目前CKD动物模型研究发现Klotho恢复可改善肾病和肾外并发症[57]，这提示我们可以通过对Klotho实施外源性干预，发挥其肾脏和肾外组织的保护作用，对CKD治疗很有前途。总之，FGF-23/Klotho的发现及其与CKD相互关系的深入研究提升了我们对CKD-MBD的理解，为CKD-MBD的诊断和治疗开拓了新的前景。我们未来的研究主题仍然是FGF-23/Klotho轴作为CKD及其并发症诊断和治疗新靶点的临床实用性和可靠性。
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Research status and the development of FGF-23/Klotho axis and chronic kidney disease
ZHU Wansheng1reviewing WU Daoquan1、2, YANG Ge2checking
(1 Southwest Medical University, Luzhou 646000, Sichuan, China;2 Neijiang Second People’s Hospital, Neijiang 641100, Sichuan, China)
【Abstract】Fibroblast growth factor-23 (FGF-23) is one kind of osteogenic hormone that can adjust the metabolism of phosphor and 1,25(OH)2D. FGF-23 combines with fibroblast growth factor receptors 1 (FGFR1) by coordinating with co-receptor Klotho and maintains serum phosphor within normal limits by increasing renal excretion of phosphor. Besides, FGF-23 can reduce synthesis of 1,25(OH)2D and promotes its degradation to reduce intestinal absorption of phosphor.Moreover, FGF-23 can reduce synthesis and secretion of parathyroid hormone, (PTH) by affecting parathyroid glands. Before serum phosphor increasing, serum FGF-23 increases obviously and serum Klotho reduces significantly with the reduction of renal function in chronic kidney disease (CKD).Current research shows that FGF-23/Klotho axis is firm related with disorders of calcium and phosphorus metabolism, secondary hyperparathyroidism (SHPT) and cardiovascular diseases (CVD) in the development of CKD.FGF-23/Klotho axis may play a key role in the development of chronic kidney disease-mineral and bone disorder (CKD-MBD).Further study on the relationship between FGF-23/Klotho axis and CKD provides a new visual angle for CKD-MBD diagnosis and treatment. This article reviews the research status and the development of FGF-23/Klotho axis and CKD.
【Key words】Fibroblast growth factor-23；Klotho；Chronic kidney disease；Secondary hyperparathyroidism
基金项目：四川省医学会科研课题(S16043)
通讯作者：吴道全，主任医师，本刊编委，E-mail:[email protected]
【中图分类号】R691
【文献标志码】A
doi：10.3969/j.issn.1672-3511.2017.04.033
(收稿日期：2017-01-03；编辑：何兴华)