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Advances in Clinical Medicine
Vol. 13  No. 05 ( 2023 ), Article ID: 65745 , 9 pages
10.12677/ACM.2023.1351158

Wnt信号通路在肾脏发育中的作用

王一凡1,2，刘爽1,2，黄春华1,2,3，汪思齐1,2,3，李茂娟2,3，汤海明1,2,3，楼迪栋1,2,3*

1贵州中医药大学基础医学院法医学教研室，贵州 贵阳

2贵州省法医中药毒理学特色重点实验室，贵州 贵阳

3贵州中医药大学司法鉴定中心，贵州 贵阳

收稿日期：2023年4月22日；录用日期：2023年5月15日；发布日期：2023年5月24日

摘要

Wnt信号通路是在胚胎发育过程中起重要作用的高度保守的信号通路，参与诱导胚胎肾脏发育，也参与了多种肾脏疾病的发生发展，且Wnt信号通路常通过经典信号通路和非经典信号通路来传递信息。当Wnt基因表达异常时会导致肾脏发育异常以及产生肾脏疾病，如先天性肾脏畸形、先天性尿路畸形、多囊肾和肾癌等。通过对不同Wnt配体基因敲除的模型和体外细胞、组织培养等的研究证明了Wnt信号通路在肾脏发育中具有必不可少的作用。此外，研究还发现在诱导肾单位的形成过程中，多种亚型的Wnt配体及其受体和转录的相关靶点表达出现上调，参与调节输尿管芽和后肾间充质的发育和分化等。本文总结了近年来Wnt信号通路在肾脏发育中的研究进展情况，以便为肾脏疾病的临床治疗提供新的方案。

关键词

Wnt信号通路，肾脏，发育，肾脏疾病

The Role of Wnt Signaling Pathway in Kidney Development

Yifan Wang1,2, Shuang Liu1,2, Chunhua Huang1,2,3, Siqi Wang1,2,3, Maojuan Li2,3, Haiming Tang1,2,3, Didong Lou1,2,3*

1Department of Forensic Medicine, School of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang Guizhou

2Key Laboratory of Traditional Chinese Medicine Toxicology in Forensic Medicine, Guiyang Guizhou

3Judicial Appraisal Center, Guizhou University of Traditional Chinese Medicine, Guiyang Guizhou

Received: Apr. 22nd, 2023; accepted: May 15th, 2023; published: May 24th, 2023

ABSTRACT

The Wnt signaling pathway is a highly conserved signaling pathway that plays an important role in embryonic development and is involved in the induction of embryonic kidney development, as well as in the development of various renal diseases, and the Wnt signaling pathway often transmits information through both classical and non-classical signaling pathways. When Wnt gene expression is abnormal, it leads to abnormal kidney development and kidney diseases such as congenital kidney malformation, congenital urogenital malformation, polycystic kidney and kidney cancer. The essential role of the Wnt signaling pathway in kidney development was demonstrated by studies on different Wnt ligand knockout models and in vitro cell and tissue cultures. In addition, it was found that the expression of multiple isoforms of Wnt ligands and their receptors and transcription-related targets appear up-regulated during the induction of renal unit formation, which is involved in regulating the development and differentiation of ureteral buds and posterior renal mesenchyme, among others. In this paper, we summarize the research progress of Wnt signaling pathway in kidney development in recent years in order to provide new options for clinical treatment of kidney diseases.

Keywords:Wnt Signaling Pathway, Kidney, Development, Kidney Disease

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. 前言

Wnt信号通路是胚胎发育过程中常见的重要信号通路，参与哺乳动物肾脏发育的调控、组织结构维持及损伤修复等多种生理过程，也是肾脏发育研究的热点 [1] 。Wnt基因家族是果蝇控制胚胎轴向发育的无翅基因Wingless在哺乳动物中的同源基因家族，目前已发现19种Wnt基因，在哺乳动物肾脏的整个发育过程中大量Wnt蛋白表达，调控肾脏发育的过程 [2] 。随着基因修饰技术的普及，转基因和基因敲除小鼠模型被越来越多的应用于肾脏发育的研究，这些研究又与对非洲爪蛙、斑马鱼和人类疾病中的发现相互印证，揭示了Wnt信号通路在脊椎动物肾脏发育过程中扮演的重要角色。本文将近年来Wnt通路在肾脏发育中的研究进展情况了总结。

2. Wnt信号通路

Wnt信号通路可分为经典的Wnt信号通路和非经典的Wnt信号通路。

2.1. 经典信号通路和非经典信号通路

2.1.1. 经典的Wnt信号通路

经典的Wnt信号通路指即β-连环蛋白(β-Catenin)依赖性信号通路。β-环连蛋白(是一种多功能蛋白，既是结构蛋白又是一种转录因子，其功能和细胞定位与Wnt配体的激活密切相关 [3] 。E-钙粘蛋白(E-Cadherin)通过其胞内结构域与β-环连蛋白结合，并进一步通过α-环连蛋白(α-Catenin)与F-actin结合从而与细胞骨架相连，参与细胞黏附连接的形成 [4] 。在Wnt通路未激活情况下，细胞质中支架蛋白(Axin)、APC蛋白以及糖原合成酶激酶3β (glycogen synthetase kinase 3β, GSK3β)组成破坏复合体，介导β-环连蛋白磷酸化，磷酸化的β-环连蛋白经泛素化-蛋白酶体途径降解 [1] 。当Wnt配体与细胞膜表面的受体卷曲蛋白(frizzled, FZD)结合，并与低密度脂蛋白相关蛋白-5 (LRP5)和LRP6组成受体复合体，可驱动胞内DVL (Dishevelled protein)向破坏复合体聚集，抑制β-环连蛋白的降解。随着胞质内β-环连蛋白的累积，β-环连蛋白被转运进入细胞核，与T细胞因子(T Cell Factor, TCF)和淋巴增强因子(Lym-phoid Enhancing Factor, LEF)转录因子形成复合体，启动Wnt依赖的基因表达，实现Wnt信号通路的激活 [4] 。

2.1.2. 非经典Wnt信号通路

非经典Wnt信号通路是不依赖β-环连蛋白的信号转导过程。如Wnt/PCP信号转导，Wnt蛋白与细胞表面的FZD跨膜受体结合，然后通过DVL蛋白激活小GTPases和C-Jun氨基末端激酶(JNK)，参与细胞骨架组织和基因表达的调控，在上皮细胞和间充质细胞结构变化过程中的定向信息传递和极性产生有重要作用 [5] 。另一种非经典Wnt信号通路是Wnt/Ca2+通路，Wnt蛋白与细胞表面的FZD跨膜受体结合后激活G蛋白而活化磷脂酶-C (PLC)，PLC进一步通过释放IP3促使细胞释放Ca2+，导致环鸟苷酸(cGMP)水平降低，钙调神经磷酸酶(Calcineurin, CaN)和蛋白激酶-C (PKC)被激活 [6] 。这些过程刺激核因子NFAT和其他转录因子，如环磷腺苷效应元件结合蛋白(cAMP Response Element-Binding Protein-1, CREB) [6] 。

2.2. Wnt蛋白的分泌

Wnt蛋白是一种分泌蛋白，作为旁分泌和自分泌的配体激活信号通路。Wnt蛋白在粗面内质网合成，通过O-酰基转移酶完成棕榈酰基修饰。脂化后的Wnt蛋白与跨膜蛋白Wnless (Wls)结合，经高尔基体运输分泌 [7] 。由于脂酰基的疏水性，分泌的Wnt通过与脂蛋白或蛋白多糖结合而黏附于细胞膜上 [8] 。

2.3. Wnt信号通路受体

与Wnt蛋白结合的受体复合体由FZD、LRP5和LRP6三种蛋白组成。FZD蛋白是一种七次跨膜受体，N端富含半胱氨酸的结构域可识别Wnt蛋白，七次跨膜结构域可以将Wnt蛋白固定在FZD蛋白表面 [9] [10] 。LRP5和LRP6都是单次跨膜蛋白，两种蛋白有高度同源性，与FZD结合形成受体复合体，是激活Wnt/β-环连蛋白信号通路必不可少的 [11] 。Wnt蛋白与受体FZD家族蛋白和LRP5/6受体结合，会失活GSK3β并阻止破坏复合体的组装，使β-连环素的降解被抑制，从而积累β-连环素并转运到细胞核 [12] 。肾素受体(PRR)也调节细胞Wnt/β-环连蛋白信号通路，PRR由Wnt/β-环连蛋白信号通路激活诱导表达，是经典的Wnt信号的放大器，同时也是FZD-LRP5或FZD-LRP6受体复合体信号转导所必需的 [13] 。实验表明，PRR敲除的转基因小鼠不能存活，这进一步突显了PRR作为辅助受体的重要性 [14] 。除LRP5和LRP6外，受体酪氨酸激酶样孤儿受体1 (Receptor tyrosine kinase-like Orphan Receptor1, ROR1)和ROR2也可作为Wnt受体，在非经典的Wnt通路中发挥作用 [15] 。

3. Wnt蛋白家族与肾单位的形成

多种Wnt蛋白家族成员参与了肾脏发育过程不同阶段，并发挥着重要作用。在小鼠胚胎的发育过程中，经典Wnt通路下游的TCF转录因子最先出现在E11.5天的输尿管芽中，大量表达出现在E13到E15天胚胎的输尿管芽和后肾间充质上皮细胞中，并且这些信号在发育成熟的肾脏中迅速减少，在出生后表达消失 [16] 。通过对不同亚型Wnt敲除的转基因小鼠的研究证明了Wnt信号通路参与了诱导帽状间充质的发育和肾单位的成熟过程。

3.1. Wnt9b能够促进输尿管芽和后肾间充质的发育成熟

在肾脏形成的过程中，输尿管芽和后肾间充质接触并相互诱导是肾脏发育关键过程。体外培养分离的输尿管芽和后肾间充质会产生两种组织退化，但通过外源性的Wnt信号和其他生长因子的刺激可促进分离后的后肾间充质继续发育 [17] [18] 。在小鼠肾脏发育过程中，Wnt9b基因最初在输尿管芽中表达，后肾发育阶段输尿管芽的顶端和茎表达，并一直保持表达到成年 [19] 。Wnt9b作为输尿管芽源性的细胞因子，可以诱导帽状间充质从干细胞表型进一步分化为永久性的肾单位细胞谱系 [20] 。同时，输尿管芽表达的Wnt9b启动帽状间充质中Wnt4、Fgf8、Pax8、Lhx1基因的表达，进一步调节肾脏的发育 [20] [21] [22] [23] 。

3.2. Wnt4促进后肾间充质的发育

表达Wnt1、Wnt3a、Wnt4、Wnt7a和Wnt7b的细胞系，能够诱导分离培养的后肾间充质，促进其进一步分化 [18] ，其中Wnt4是诱导帽状间充质发育过程中最主要的必须性内源性Wnt家族蛋白 [21] 。Wnt4能够诱导肾后间充质细胞的聚集，促进肾后间充质细胞发生间充质上皮转换(Mesenchymal to Epithelial Transition, MET)，发育成肾单位 [21] 。而细胞命运图谱研究表明，成熟的肾单位完全由表达Wnt4基因的细胞后代组成 [24] 。对非洲爪蛙的研究中也发现，xWnt4主要表达于前肾的原基和肾脏发育后期的肾小管顶端，参与了非洲爪蛙的前肾小管发育和小鼠的肾脏发育过程 [25] 。Wnt4基因敲除的斑马鱼模型肾单位会在形成肾小管前聚体之前停止分化，最终只能形成残缺的肾脏 [21] 。总之，输尿管芽表达的Wnt9b会诱导帽状间充质中Wnt4的表达增高，而Wnt4会进一步促进后肾间充质的发育，这一系列反应在肾后间充质的聚集和发育中起着重要作用。

3.3. Wnt11促进肾脏的集合管发育

输尿管芽分化过程中产生的分支是决定最终肾单位数量的关键因素，而肾单位的数量对成人肾脏的大小起决定作用。胶质细胞源神经营养因子(GDNF)依赖的信号转导能够促进集合管系统的形成。在肾脏发育的最初阶段，帽状间充质表达GDNF，通过原癌基因(RET)向输尿管芽发出信号，促进输尿管芽向内生长和分支形成，GDNF或RET的表达发生改变都会影响肾脏的生长发育 [26] [27] 。Wnt11在发育的输尿管芽末端表达 [28] ，能够激活GDNF/RET通路共同促进集合管的发育 [29] 。但与Wnt1、Wnt3a、Wnt4、Wnt7a和Wnt7b不同，Wnt11不能诱导体外的后肾间充质组织发育 [18] 。非洲爪蛙所分泌的Wnt11b可以诱导其肾脏的形成，但哺乳动物的Wnt11b在进化过程中丢失，这可能是哺乳动物前肾退化的原因 [30] 。Wnt11敲除的转基因小鼠肾单位数量明显变少，肾脏体积缩小 [29] 。Wnt11功能的缺失会延迟输尿管芽的第一个分支形成的时间，同时帽状间充质中表达的GDNF出现短时间的减少。而用外源性的GDNF刺激分离到体外的后肾，发现输尿管芽尖端中的Wnt11表达增加，说明Wnt11和GDNF/RET通路在小鼠肾脏发育中形成了一个正反馈信号环路，有助于产生足够数量的输尿管芽分支并形成集合管系统，诱导相应数量的肾单位产生 [31] 。

3.4. Wnt7b和Wnt4促进肾脏的髓质发育

血浆在皮质滤过后形成原尿，在髓质进行渗透压调节，以及部分物质的分泌与重吸收。肾髓质主要由髓袢和集合管构成，它们在肾脏呈放射状分布，为肾脏发挥其分泌和排泄功能提供结构基础。Wnt7b一般会在输尿管芽的茎中表达，也有诱导体外分离的后肾间充质分化的能力 [18] 。敲除输尿管芽细胞中的Wnt7b基因不会影响肾单位的形成，但髓质会发生退化，表示肾髓质的形成与肾单位的形成没有直接联系 [2] 。Wnt7b敲除的转基因小鼠肾脏大小接近正常，输尿管芽分支的尖端数量没有明显变化，但髓质中的髓袢出现断裂和发育不全，近端的输尿管芽管腔也出现扩张 [2] 。当输尿管芽表达的Wnt7b拮抗蛋白Dickkopf相关蛋白1 (Dickkopf-1)受到抑制时，肾髓质会出现过度生长，这些表明肾脏髓质的发育取决于Wnt7b与拮抗蛋白Dickkopf-1之间的动态平衡 [32] 。Wnt4也同样在发育肾脏的髓质表达，Wnt4基因敲除大鼠髓质中Bmp4的表达降低，会促进分化标志物平滑肌肌动蛋白(α-SMA)的表达降低，提示髓质中的周细胞分化失败 [33] 。这些研究表明，Wn7b和Wnt4两种蛋白参与协调肾脏髓质发育。

3.5. Wnt5a在早期肾脏发育中的作用

近期研究发现，非典型Wnt5a/Ror2信号通路会诱导后肾间充质的分化，影响肾脏形态 [34] 。Wnt5a基因敲除的斑马鱼会出现肾小球囊肿和肾小管扩张，Wnt5a基因敲除的小鼠肾脏表型严重受损，多种组织的发育和分化出现紊乱，如肾脏发育不全、融合肾、肾积水和输尿管发育畸形，导致先天性肾和尿路畸形 [35] 。

4. Wnt/β-环连蛋白信号通路与肾脏发育的关系

Wnt/β-环连蛋白信号通路中的多种蛋白都参与了肾脏发育的过程。LRP6基因敲除的小鼠会表现出泌尿生殖系统的缺陷和囊性肾发育不全，表明Wnt通路的受体LRP6参与了肾脏早期的发育过程 [36] 。FZD受体也与肾脏的发育有密切关系，非洲爪蛙的xFrizzled8 (xFZ8)受体的基因表达抑制可造成前肾小管的分支出现明显缺陷，表明xFZ8维持前输尿管芽和肾小管的正常上皮结构有重要意义 [37] ，而FZD4和FZD8基因敲除的小鼠也表现出输尿管芽生长紊乱和肾脏体积减小 [38] 。锂作为Wnt信号的激动剂，能通过抑制GSK-3β的表达使β-环连蛋白增多，可在体外诱导后肾间充质细胞出现上皮分化，而另一种GSK-3β的抑制剂6-溴靛玉红-3'-肟(BIO)处理体外后肾间充质组织则出现大量的上皮样改变和肾单位的完全分离 [39] 。同样，上调β-环连蛋白、LEF1和TCF1的表达也能诱导体外的后肾间充质组织肾单位出现分化，提示这些Wnt/β-环连蛋白信号通路相关蛋白都在肾脏发育过程中发挥作用 [40] 。

在小鼠胚胎E6.5天时即可检测到β-环连蛋白的表达，参与了前后轴、原始条纹和中胚层的形成 [41] 。体内外的研究表明，Six2和LEF/TCF转录因子结合形成调节复合物，能够维持祖细胞形态，而β-环连蛋白进入该复合物后，激活Wnt经典通路促进靶基因转录，促进肾脏发育，故Six2和LEF/TCF转录因子形成的复合体能够调控着肾单位祖细胞维持和肾脏发育之间的平衡 [42] 。在特异性输尿管芽β-环连蛋白基因敲除的小鼠发育过程中，不同分支的肾小管上皮细胞形态异常，会产生肾脏功能发育不良 [43] 。大鼠胚胎肾脏体外培养上皮细胞分化的过程中，β-环连蛋白/TCF的下游基因如细胞周期蛋白d1 (Cyclin d1)和Emx2的表达增加 [44] 。在发育过程中敲除肾脏的β-环连蛋白基因，小鼠会出现肾功能异常、肾实质发育不良、肾小管浅层缺失，以及肾小囊上皮细胞缺失等表型 [45] 。这些结果表明，Wnt/β-环连蛋白信号在肾脏发育阶段发挥了不可或缺的作用。

5. Wnt/PCP信号通路与肾单位的形成

近年来不断有证据证明Wnt/PCP信号通路在肾脏的发育和发挥生理功能中起着关键作用。平面细胞极性通路(Planar Cell Polarity, PCP)可以通过小GTPases、Daam1和c-Jun等下游效应分子起作用，参与细胞骨架的组装、细胞增殖和纤毛发生等活动。PCP过程中的核心基因如Vangl2，Celsr1，Fzd3/6和Dvl1/2表达的缺失会导致细胞定向分裂的丧失，细胞出现汇集延伸，最终导致囊性肾病的发生 [46] 。PCP的一些蛋白会在肾脏发育中的上皮细胞中表达，在细胞分裂方向、运动、黏附和对成熟肾脏的形态发生的过程中发挥作用 [47] 。研究表明PCP主要在输尿管芽分支和伸长的过程中发挥作用，最终决定输尿管芽的管径、长度和形状。

Wnt5a、Wnt7b、Wnt9b和Wnt11是PCP途径的Wnt配体，这些配体基因敲除的小鼠模型都会表现出输尿管芽分支的缺陷 [47] 。中胚层来源的肾小管上皮细胞细胞表达Wnt5a，激活Wnt5a/Ror2信号通路，这些信号调控输尿管芽的扩张。Wnt5a基因敲除小鼠肾脏中GDNF蛋白过表达，会过度刺激后肾间充质和输尿管芽的发育，使后肾间充质的定位失调，使体内出现过多且发育不成熟的肾脏和输尿管 [48] 。Wnt7b基因敲除斑马鱼也会因为髓质的集合管上皮细胞分裂平面的解体导致髓质发育出现异常，最终不能形成浓缩尿 [2] 。而Wnt9b对形成肾小管的长度和直径的影响很重要，在肾脏形态发生过程中缺少Wnt9b会扰乱上皮细胞的PCP，并导致多囊肾病(PKD)的发生 [19] 。

6. Wnt信号通路与肾脏囊肿的形成

肾小管上皮细胞中的β-环连蛋白过表达会诱导肾脏发生多囊病变。在肾小管上皮细胞过表达β-环连蛋白的小鼠表现出严重的多囊肾、肾功能异常，其表型与人常染色体显性遗传性多囊肾病(ADPKD)相似 [49] 。条件性敲除小鼠肾小管上皮细胞的APC基因后，β-环连蛋白蛋白的表达水平增高，小鼠的肾脏发育过程中有多个囊肿形成 [50] 。水通道蛋白-1 (AQP1)是肾脏近端小管和髓袢降支的分子标志物，AQP1过表达可以抑制β-环连蛋白和Cyclin d1的表达，AQP1基因敲除的胚胎肾脏的大小和囊肿数量较对照组明显增加 [51] 。Ahi1基因编码的Jouberin蛋白能够调节肾脏的Wnt信号转导Ahi1基因敲除的小鼠能够促进β-环连蛋白的表达及核聚集，并上调下游基因的转录，使肾脏发生囊性病变和畸形 [52] 。这些结果表明，Wnt-β-环连蛋白信号通路的激活参与了多囊肾脏病的发病过程。

基因突变也是多囊肾产生的原因之一，这些基因突变往往影响了肾小管上皮细胞初级纤毛的形成和Wnt蛋白的表达 [53] 。初级纤毛形成受损会导致肾小管内液体的流动和Ca2+内流出现紊乱，最终导致囊性肾病的形成 [54] 。同时，在肾小管发育的延长过程中，需要肾小管上皮细胞定向分裂，而调节细胞极性的Wnt/PCP信号通路在这一过程中发挥的作用至关重要。PCP信号能够调节肾单位的成熟和有丝分裂的方向，调节过程异常也会导致动物模型肾脏出现多囊病变 [55] 。总而言之，经典的Wnt/β-环连蛋白信号通路和非经典的Wnt/PCP信号通路均与肾脏囊性病变的形成密切相关，在肾脏发育发挥重要作用 [56] 。

7. 展望

肾脏的发育伴随着复杂而又精密的细胞间通讯过程，Wnt信号通路是主导因素之一。不同的Wnt配体在肾脏发育的不同阶段表现出特定的功能，如Wnt9b和Wnt4参与诱导帽间充质细胞发育形成肾单位，WNT11能够影响早期的输尿管芽的分支，并决定最终的肾脏大小，WNT7b参与肾脏髓质形成。而在胚胎的肾脏中也表达的Wnt2b、Wnt5a和Wnt6等Wnt配体，对于肾脏发育的作用仍不明确。其中Wnt2/Wnt2b双基因敲除小鼠的肾脏表型未出现明显改变 [57] ，提示我们Wnt2b可能不是诱导肾脏发育的关键因素。经典和非经典的Wnt信号通路都在诱导输尿管芽、肾单位的形成和进一步分化中起重要作用，而涉及到Wnt/PCP信号通路的肾脏形态转变过程需要更进一步研究。Wnt基因敲除对肾脏的表型产生严重的影响，如Wnt9b敲除的小鼠肾脏出现多囊病变，Wnt4敲除的斑马鱼不能分化出成熟的肾单位，Wnt7b敲除影响小鼠的肾髓质形成等等。这些模型提示Wnt信号转导的失败可能是人类先天性肾脏与尿路异常的原因。

综上所述，Wnt通路在输尿管芽和肾单位的诱导、分化过程中发挥了重要作用，而Wnt信号的失调会导致肾脏发生不同程度的病变，我们需要更深刻的探索Wnt信号通路在肾脏发育过程中发挥的作用，从而更好地理解肾脏各种疾病的发展过程，并通过调控Wnt信号通路，实现对各种肾脏疾病更有效的诊断和治疗。

项目基金

省教育厅特色重点实验室(黔教合KY字[2021] 004)；2020省科技支撑(黔教合支撑[2020] 4Y209)；黔教合KY字[2022] 386号。

文章引用

王一凡,刘 爽,黄春华,汪思齐,李茂娟,汤海明,楼迪栋. Wnt信号通路在肾脏发育中的作用
The Role of Wnt Signaling Pathway in Kidney Development[J]. 临床医学进展, 2023, 13(05): 8282-8290. https://doi.org/10.12677/ACM.2023.1351158

参考文献

  1. 1. Nusse, R. and Clevers, H. (2017) Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell, 169, 985-999. https://doi.org/10.1016/j.cell.2017.05.016

  2. 2. Grollman, A.P. (2013) Aristolochic Acid Nephropathy: Harbinger of a Global Iatrogenic Disease. Environmental and Molecular Mutagenesis, 54, 1-7. https://doi.org/10.1002/em.21756

  3. 3. Medina, M.A., Oza, G., Sharma, A., et al. (2020) Triple-Negative Breast Cancer: A Review of Conventional and Advanced Therapeutic Strategies. International Journal of Environmental Re-search and Public Health, 17, Article No. 2078. https://doi.org/10.3390/ijerph17062078

  4. 4. Schunk, S.J., Floege, J., Fliser, D. and Speer, T. (2021) Wnt-β-Catenin Signalling—A Versatile Player in Kidney Injury and Repair. Nature Reviews Nephrology, 17, 172-184. https://doi.org/10.1038/s41581-020-00343-w

  5. 5. Valenta, T., Hausmann, G. and Basler, K. (2012) The Many Faces and Functions of β-Catenin. The EMBO Journal, 31, 2714-2736. https://doi.org/10.1038/emboj.2012.150

  6. 6. Ma, L. and Wang, H.-Y. (2007) Mitogen-Activated Protein Kinase p38 Regulates the Wnt/Cyclic GMP/Ca2+ Non-canonical Pathway. Journal of Biological Chemistry, 282, 28980-28990. https://doi.org/10.1074/jbc.M702840200

  7. 7. Harterink, M. and Korswagen, H.C. (2012) Dissecting the Wnt Se-cretion Pathway: Key Questions on the Modification and Intracellular Trafficking of Wnt Proteins. Acta Physiologica, 204, 8-16. https://doi.org/10.1111/j.1748-1716.2011.02287.x

  8. 8. Gross, J.C., Chaudhary, V., Bartscherer, K. and Boutros, M. (2012) Active Wnt Proteins Are Secreted on Exosomes. Nature Cell Biology, 14, 1036-1045. https://doi.org/10.1038/ncb2574

  9. 9. Hsieh, J.C., Rattner, A., Smallwood, P.M. and Nathans, J. (1999) Biochemi-cal Characterization of Wnt-Frizzled Interactions Using a Soluble, Biologically Active Vertebrate Wnt Protein. Proceed-ings of the National Academy of Sciences of the United States of America, 96, 3546-3551. https://doi.org/10.1073/pnas.96.7.3546

  10. 10. Janda, C.Y., Waghray, D., Levin, A.M., Thomas, C. and Garcia, K.C. (2012) Structural Basis of Wnt Recognition by Frizzled. Science, 337, 59-64. https://doi.org/10.1126/science.1222879

  11. 11. Tamai, K., Semenov, M., Kato, Y., et al. (2000) LDL-Receptor-Related Proteins in Wnt Signal Transduction. Nature, 407, 530-535. https://doi.org/10.1038/35035117

  12. 12. Ren, Q., Chen, J. and Liu, Y. (2021) LRP5 and LRP6 in Wnt Signaling: Similarity and Divergence. Frontiers in Cell and Developmental Biology, 9, Article 670960. https://doi.org/10.3389/fcell.2021.670960

  13. 13. Li, Z., Zhou, L., Wang, Y., et al. (2017) (Pro)Renin Receptor Is an Amplifier of Wnt/β-Catenin Signaling in Kidney Injury and Fibrosis. Journal of the American Society of Nephrology, 28, 2393-2408. https://doi.org/10.1681/ASN.2016070811

  14. 14. Riediger, F., Quack, I., Qadri, F., et al. (2011) Prorenin Receptor Is Essential for Podocyte Autophagy and Survival. Journal of the American Society of Nephrology, 22, 2193-2202. https://doi.org/10.1681/ASN.2011020200

  15. 15. Oishi, I., Suzuki, H., Onishi, N., et al. (2003) The Receptor Tyro-sine Kinase Ror2 Is Involved in Non-Canonical Wnt5a/JNK Signalling Pathway. Genes to Cells, 8, 645-654. https://doi.org/10.1046/j.1365-2443.2003.00662.x

  16. 16. Iglesias, D.M., Hueber, P.A., Chu, L., et al. (2007) Ca-nonical WNT Signaling during Kidney Development. American Journal of Physiology-Renal Physiology, 293, F494-F500. https://doi.org/10.1152/ajprenal.00416.2006

  17. 17. Saxén, L. and Sariola, H. (1987) Early Organogene-sis of the Kidney. Pediatric Nephrology, 1, 385-392. https://doi.org/10.1007/BF00849241

  18. 18. Kispert, A., Vainio, S. and McMahon, A.P. (1998) Wnt-4 Is a Mesen-chymal Signal for Epithelial Transformation of Metanephric Mesenchyme in the Developing Kidney. Development, 125, 4225-4234. https://doi.org/10.1242/dev.125.21.4225

  19. 19. Karner, C., Chirumamilla, R., Aoki, S., et al. (2009) Wnt9b Signaling Regulates Planar Cell Polarity and Kidney Tubule Morphogenesis. Nature Genetics, 41, 793-799. https://doi.org/10.1038/ng.400

  20. 20. Carroll, T.J., Park, J.S., Hayashi, S. Majumdar, A. and McMahon, A.P. (2005) Wnt9b Plays a Central Role in the Regulation of Mesenchymal to Epithelial Transitions Underlying Organogenesis of the Mammalian Urogenital System. Developmental Cell, 9, 283-292. https://doi.org/10.1016/j.devcel.2005.05.016

  21. 21. Stark, K., Vainio, S., Vassileva, G. and McMahon, A.P. (1994) Epithelial Transformation of Metanephric Mesenchyme in the Developing Kidney Regulated by Wnt-4. Nature, 372, 679-683. https://doi.org/10.1038/372679a0

  22. 22. Grieshammer, U., Cebrián, C., Ilagan, R., et al. (2005) FGF8 Is Required for Cell Survival at Distinct Stages of Nephrogenesis and for Regulation of Gene Expression in Nascent Neph-rons. Development, 132, 3847-3857. https://doi.org/10.1242/dev.01944

  23. 23. Kobayashi, A., Kwan, K.-M., Carroll, T.J., et al. (2005) Distinct and Se-quential Tissue-Specific Activities of the LIM-Class Homeobox Gene Lim1 for Tubular Morphogenesis during Kidney Development. Development, 132, 2809-2823. https://doi.org/10.1242/dev.01858

  24. 24. Shan, J., Jokela, T., Skovorodkin, I. and Vainio, S. (2010) Mapping of the Fate of Cell Lineages Generated from Cells That Express the Wnt4 Gene by Time-Lapse during Kidney Development. Differentiation, 79, 57-64. https://doi.org/10.1016/j.diff.2009.08.006

  25. 25. Saulnier, D.M.E., Ghanbari, H. and Brändli, A.W. (2002) Essential Function of Wnt-4 for Tubulogenesis in the Xenopus Pronephric Kidney. Developmental Biology, 248, 13-28. https://doi.org/10.1006/dbio.2002.0712

  26. 26. Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini, F. and Pachnis, V. (1994) Defects in the Kidney and Enteric Nervous System of Mice Lacking the Tyrosine Kinase Receptor Ret. Nature, 367, 380-383. https://doi.org/10.1038/367380a0

  27. 27. Sánchez, M.P., Silos-Santiago, I., Frisén, J., et al. (1996) Renal Agenesis and the Absence of Enteric Neurons in Mice Lacking GDNF. Nature, 382, 70-73. https://doi.org/10.1038/382070a0

  28. 28. Lako, M., Strachan, T., Bullen, P., et al. (1998) Isolation, Characterisation and Embryonic Expression of WNT11, a Gene Which Maps to 11q13.5 and Has Possible Roles in the Development of Skeleton, Kidney and Lung. Gene, 219, 101-110. https://doi.org/10.1016/S0378-1119(98)00393-X

  29. 29. Majumdar, A., Vainio, S., Kispert, A., McMahon, J. and McMahon, A.P. (2003) Wnt11 and Ret/Gdnf Pathways Cooperate in Reg-ulating Ureteric Branching During Metanephric Kidney Development. Development, 130, 3175-3185. https://doi.org/10.1242/dev.00520

  30. 30. Tételin, S. and Jones, E.A. (2010) Xenopus Wnt11b Is Identified as a Po-tential Pronephricinducer. Developmental Dynamics, 239, 148-159. https://doi.org/10.1002/dvdy.22012

  31. 31. Pepicelli, C.V., Kispert, A., Rowitch, D.H. and McMahon, A.P. (1997) GDNF Induces Branching and Increased Cell Proliferation in the Ureter of the Mouse. Developmental Biology, 192, 193-198. https://doi.org/10.1006/dbio.1997.8745

  32. 32. Pietilä, I., Ellwanger, K., Railo, A., et al. (2011) Secreted Wnt Antag-onist Dickkopf-1controls Kidney Papilla Development Coordinated by Wnt-7b Signalling. Developmental Biology, 353, 50-60. https://doi.org/10.1016/j.ydbio.2011.02.019

  33. 33. Itäranta, P., Chi, L., Seppänen, T., et al. (2006) Wnt-4 Signaling is Involved in the Control of Smooth Muscle Cell Fate via Bmp-4 in the Medullary Stroma of the Developing Kidney. De-velopmental Biology, 293, 473-483. https://doi.org/10.1016/j.ydbio.2006.02.019

  34. 34. Lyons, J.P., Mueller, U.W., Ji, H., Everett, C., Fang, X., Hsieh, J.C., Barth, A.M. and McCrea, P.D. (2004) Wnt-4 Activates the Canonical β-Catenin-Mediated Wnt Pathway and Binds Frizzled-6 CRD: Functional Implications of Wnt/β-Catenin Activity in Kidney Epithelial Cells. Experimental Cell Re-search, 298, 369-387. https://doi.org/10.1016/j.yexcr.2004.04.036

  35. 35. Pietilä, I., Prunskaite-Hyyryläinen, R., Kaisto, S., et al. (2016) Wnt5a Deficiency Leads to Anomalies in Ureteric Tree Development, Tubular Epithelial Cell Organization and Basement Membrane Integrity Pointing to a Role in Kidney Collecting Duct Patterning. PLOS ONE, 11, e0147171. https://doi.org/10.1371/journal.pone.0147171

  36. 36. Wang, Y., Stokes, A., Duan, Z., et al. (2016) LDL Recep-tor-Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia. Journal of the American Society of Nephrology, 27, 417-427. https://doi.org/10.1681/ASN.2014100998

  37. 37. Satow, R., Chan, T.-C. and Asashima, M. (2004) The Role of Xenopus Frizzled-8 in Pronephric Development. Biochemical and Biophysical Research Communications, 321, 487-494. https://doi.org/10.1016/j.bbrc.2004.06.166

  38. 38. Ye, X., Wang, Y., Rattner, A. and Nathans, J. (2011) Genetic Mo-saic Analysis Reveals a Major Role for Frizzled 4 and Frizzled 8 in Controlling Ureteric Growth in the Developing Kid-ney. Development, 138, 1161-1172. https://doi.org/10.1242/dev.057620

  39. 39. Davies, J.A. and Garrod, D.R. (1995) Induction of Early Stages of Kidney Tubule Differentiation by Lithium Ions. Developmental Biology, 167, 50-60. https://doi.org/10.1006/dbio.1995.1006

  40. 40. Kuure, S., Popsueva, A., Jakobson, M., Sainio, K. and Sariola, H. (2007) Glycogen Synthase Kinase-3 Inactivation and Stabilization of β-Catenin Induce Nephron Differentiation in Isolat-ed Mouse and Rat Kidney Mesenchymes. Journal of the American Society of Nephrology, 18, 1130-1139. https://doi.org/10.1681/ASN.2006111206

  41. 41. Mohamed, O.A., Clarke, H.J. and Dufort, D. (2004) β-Catenin Signaling Marks the Prospective Site of Primitive Streak Formation in the Mouse Embryo. Developmental Dynamics, 231, 416-424. https://doi.org/10.1002/dvdy.20135

  42. 42. Park, J.S., Ma, W., O’Brien, L.L., et al. (2012) Six2 and Wnt Regulate Self-Renewal and Commitment of Nephron Progenitors through Shared Gene Regulatory Networks. De-velopmental Cell, 23, 637-651. https://doi.org/10.1016/j.devcel.2012.07.008

  43. 43. Marose, T.D., Merkel, C.E., McMahon, A.P. and Carroll, T.J. (2008) β-Catenin Is Necessary to Keep Cells of Ureteric Bud/wolffian Duct Epithelium in a Precursor State. Develop-mental Biology, 314, 112-126. https://doi.org/10.1016/j.ydbio.2007.11.016

  44. 44. Schmidt-Ott, K.M., Masckauchan, T.N., Chen, X., et al. (2007) β-Catenin/TCF/Lef Controls a Differentiation-Associated Transcriptional Program in Renal Epithelial Progenitors. De-velopment, 134, 3177-3190. https://doi.org/10.1242/dev.006544

  45. 45. Grouls, S., Iglesias, D.M., Wentzensen, N., et al. (2012) Lineage Specifi-cation of Parietal Epithelial Cells Requires β-Catenin/Wnt Signaling. Journal of the American Society of Nephrology, 23, 63-72. https://doi.org/10.1681/ASN.2010121257

  46. 46. PPapakrivopoulou, E., Dean, C.H., Copp, A.J. and Long, D.A. (2014) Planar Cell Polarity and Thekidney. Nephrology Dialysis Transplantation, 29, 1320-1326. https://doi.org/10.1093/ndt/gft484

  47. 47. Carroll, T.J. and Das, A. (2011) Planar Cell Polarity in Kidney Develop-ment and Disease. Organogenesis, 7, 180-190. https://doi.org/10.4161/org.7.3.18320

  48. 48. Nishita, M., Qiao, S., Miyamoto, M., et al. (2014) Role of Wnt5a-Ror2 Signaling in Morphogenesis of the Metanephric Mesenchyme during Ureteric Budding. Molecular and Cellular Biology, 34, 3096-3105. https://doi.org/10.1128/MCB.00491-14

  49. 49. Saadi-Kheddouci, S., Berrebi, D., Romagnolo, B., et al. (2001) Early Development of Polycystic Kidney Disease in Transgenic Mice Expressing an Activated Mutant of the β-Catenin Gene. Oncogene, 20, 5972-5981. https://doi.org/10.1038/sj.onc.1204825

  50. 50. Qian, C.-N., Knol, J., Igarashi, P., et al. (2005) Cystic Renal Neoplasia Following Conditional Inactivation of Apc in Mouse Renal Tubular Epithelium. Journal of Biological Chemistry, 280, 3938-3945. https://doi.org/10.1074/jbc.M410697200

  51. 51. Wang, W., Li, F., Sun, Y., et al. (2015) Aquaporin-1 Retards Renal Cyst Development in Polycystic Kidney Disease by Inhibition of Wnt Signaling. The FASEB Journal, 29, 1551-1563. https://doi.org/10.1096/fj.14-260828

  52. 52. Lancaster, M.A., Louie, C.M., Silhavy, J.L., et al. (2009) Impaired Wnt-β-Catenin Signaling Disrupts Adult Renal Homeostasis and Leads to Cystic Kidney Ciliopathy. Nature Medicine, 15, 1046-1054. https://doi.org/10.1038/nm.2010

  53. 53. Bergmann, C., Guay-Woodford, L.M., Harris, P.C., et al. (2018) Polycystic Kidney Disease. Nature Reviews Disease Primers, 4, Article No. 50. https://doi.org/10.1038/s41572-018-0047-y

  54. 54. Simons, M. and Walz, G. (2006) Polycystic Kidney Disease: Cell Division without a c(l)ue? Kidney International, 70, 854-864. https://doi.org/10.1038/sj.ki.5001534

  55. 55. Fischer, E., Legue, E., Doyen, A., et al. (2006) Defective Planar Cell Polarity in Polycystic Kidney Disease. Nature Genetics, 38, 21-23. https://doi.org/10.1038/ng1701

  56. 56. Lancaster, M.A. and Gleeson, J.G. (2010) Cystic Kidney Disease: The Role of Wnt Signaling. Trends in Molecular Medicine, 16, 349-360. https://doi.org/10.1016/j.molmed.2010.05.004

  57. 57. Goss, A.M., Tian, Y., Tsukiyama, T., et al. (2009) Wnt2/2b and β-Catenin Signaling Are Necessary and Sufficient to Specify Lung Progenitors in the Foregut. Developmental Cell, 17, 290-298. https://doi.org/10.1016/j.devcel.2009.06.005

    58. NOTES

    *通讯作者。

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