分子细胞生物学报英文稿

中国细胞生物学学报(原名:细胞生物学杂志)分子细胞生物学报 Journal of Molecular Cell Biology

Congenital kidney maldevelopment and molecular biology research The abstract kidney maldevelopment is the kidney has theunusual clinical consequence, its typical histo-pathologycharacteristic is appears originally Beginning kidney pellet and 肾小管, 软骨样 metaplasia andso on. In recent years through application molecular technology and soon target gene and home position clone Has the molecular regulation mechanism research to the normalmammal kidney, has to the congenital kidney maldevelopmentpathogenesis More understandings. This article will make a discussion to thecongenital kidney maldevelopment molecular biology research recentsituation, and will be right Including the growth factor several kind of gene mutation,copies the regulative barrier and the expression change and the kidneysends the good relations Carries on the discussion. The kidney maldevelopment is the kidney has not been able to carry onthe congenital disease which the normal growth growth forms, in thepast arose to it The mechanism understanding are really few, along with themember biological technology development and the application, expoundsthe kidney occurrence from the member study mechanism Had a more thorough understanding from the molecular biologylevel to the kidney maldevelopment occurrence. This article onshort-term regarding this question The research progress makes an introduction. 1 kidney occurs with the kidney maldevelopment Before the normal mammalia kidney is located between liesbetween 中胚层, 中胚层 the differentiation forms the kidneydrive pipe, after further tempts Leads forms 中肾 the drive pipe to the ureter bud, under theureter bud induction, end the embrionic body two sides fresh reninssplits up into after The kidney 胚基, the kidney embryonic development isprecisely completes by the ureter bud and the latter kidney 胚基 twoparts, former gradually grows Becomes 肾盂, 肾盏 and 集合管, latter grows肾小管and the kidney pellet, finally 肾小管and集合管docking, Constitutes normally 肾单位. If the ureter bud and thelatter kidney 胚基 two parts cannot grow according to the normaldegree and implement rightly Meets namely creates the kidney maldevelopment. The kidneymaldevelopment may be partial, also may be complete. Most types The kidney maldevelopment partner has the cyst, prompts themaldevelopment each kind of form to have machine-made together in theformation. On clinical common congenital kidney maldevelopment including multi-pouches, obstruction kidney maldevelopment as well as with gene The related kidney growth is unusual. The histo-pathologyimportant characteristic appears primitive 肾小管and the metaplasiacartilage. Complete list The side kidney maldevelopment, may display for does not havethe symptom. In most maldevelopment case of illness, the kidney flawis the double side, prompts Gene mutation in normal kidney growth vital role. Shan Cexingdisease then possibly is one kind of obtaining damage is the resultof, This damage destroyed the gene normal expression, thenaffected maturely had the vital significance to the kidney the proteinproduction. 2 kidneys maldevelopment common type congenital multi- pouches kidneys maldevelopment The multi- pouches kidney maldevelopment (multiple cystichypoplastic) is one common completeness The kidney maldevelopment, are many for the single sidepathological change (14-20% for double side nature), contracts thekidney to lose the normal shape, irregular The size cyst replaces, the kidney function loses and oftenthe partner has the ureter obstruction, is newborn abdomen Bao Kuaizuicommon One of reasons. The multi- pouches maldevelopment kidney outlook assumes thekidney-shaped structure, the most case of illness partner has a 闭锁ureter. Pregnancy The early polycystic kidney includes the normal growth to havethe ingredient, loses the urine including the induction after kidney胚基 island and the branch The tube drive pipe, may distinguish the pouch change in thisstage 肾单位 each Duan Yijun [ 1 ]. After lives the multi- pouchesmaldevelopment kidney The histo-pathology variation including the primitive肾小管pouch change, expands also the disarrangement of thestructure, has around the obvious tube Response nature, textile fiber myo- link formation, cartilageingredient as symbol organization transformation and so on. congenital obstructions kidneys maldevelopment The congenital urine road obstruction in dissects in theposition often to occur to the ureter and urinary bladder 连接处,after congenitalness The urethra valve is the babies and infants uninary systemobstruction important reason. Congenital obstruction kidney histologycharacteristic and multi- pouches The kidney maldevelopment is similar, including 肾单位 eachDuan Rushen the pellet pouch transformation, the nature expands alsothe disarrangement of the structure, the marrow The nature and the straight small blood vessel remarkablehypoplasia, has around the tube the textile fiber myo- link, the manykinds of forms kidney pellet and the growth kidney Unit each section. Is same with the multi- pouches kidneymaldevelopment, the congenital obstruction kidney performance is aseries of diseases, its degree and The embryonic period urine 流阻 related fills the time whichoccurs [ 2 ]. The table partner has the kidney to grow the unusual syndrome ------------------------------------------------------ Syndrome chromosome heredity form ------------------------------------------------------ The tip and refers to (foot) to be abnormal (Apert ' s)常染色体 the dominance Sends chest gallery malnutrition 常染色体 recessivenesswhich suffocates Obese, reproduction hypofunction and so on 常染色体recessiveness Gill - ear - kidney 常染色体 dominance Campomelic growth exceptionally 常染色体 recessiveness Brain - liver - kidney (Passarge ' s) 常染色体recessiveness Fryns ' s 常染色体 recessiveness Goemine ' s X- connection Goldston (hereditary blood capillary expands) 常染色体recessiveness? Hall-Pallster ' s sending out Ivemark ' s 常染色体 recessiveness Marden-Walker ' s 常染色体 recessiveness Mecket-Gruber 常染色体 recessiveness Miranda ' s 常染色体 recessiveness Senlor-Loken ' s 常染色体 recessiveness? Three bodies chromosomes 16-18 (Edwards) Three bodies chromosomes 13-15 (Patau) Three bodies chromosomes 21 (Down) 结节性 hardened 常染色体 dominance Von Hippel-Lindau 常染色体 dominance ------------------------------------------------------ kidneys maldevelopment syndrome The kidney maldevelopment syndrome is includes kidney abnormalthe and so on pouch maldevelopment hereditary indication group (seesthe table ). Presently expounds a part of syndromes its special gene andthe protein flaw. The maldevelopment phenotype apparent rate assumes Presently a band, prompts has other gene influence kidneysfinally 表型. The maldevelopment usually all contains the many kindsof organs, Explained the flaw the gene involves the normal organogenesisthe foundation. The histo-pathology discovered that, this kind ofsyndrome light is possible Appears the great pouch to form (for example 结节性hardening), heavy possibly appears the pouch growth exceptionally withthe renal failure (Meckel- Gruber syndrome). 3 kidneys maldevelopment molecular biology The present research discovery has the many kinds of genes andthe kidney maldevelopment related, like WT-1, Pax-2, GDNF, B Gene and so on F-2, BMP-7, PDGF, Wnt-4 in after kidney 胚基expression. Pax-2, c-ret, BMP-7, alpha 3 beta 1 and so on in ureter bud expression. When these genes lack ordestroys, the kidney cannot normally occur with the growth [ 3 ]. Sonnenberg and so on [ 4 ] 补体 RNA and the DNA probeconducts the research with the specificity immune body and theemission mark, the determination Multi- peptides growth factor, heparin structure growth factorand their acceptor, extracellular matrix member and cell surfaceentire Gathers gene and so on element in the kidney growth specificexpression position. For example liver cell growth factor mainly inafter kidney embryo gene Expression, but its acceptor c-met in ureter plumule epidermisexpression. This kind of peptides and its the acceptor are thin in twokind of types On butcher's expression explanation ureter drive pipe formsthe induction to the after 肾间 archery target. Schuchardt and so on[ 5 ] passes Using the gene recombination and the preparation 纯合子invalid sudden change mouse, discovers some influence kidney growththe gene and the multi- peptides, like The shift growth factor - beta, the liver cell growth factor,the insulin type growth factor - II, according to saw finally shows The inference specific gene has the function in the normalkidney. Tyrosine activating enzyme body acceptor c-ret leads in thebranch ureter The tube as well as matches in the nerve nutrition factorwhich the body - neuroglia grows to express. When the mouse c-ret geneis destroyed, leads Sends the entire kidney maldevelopment. Copies the factor genecode protein to be able with the DNA union, moreover has regulatesother gene tables Reaches function. In the mammal kidney growth, Wilms ' tumorgene WT-1 and Pax2 code copies the factor, Its expression form influence kidney cell differentiation [ 6,7 ]. The gene syndrome and the kidney form exceptionally related, inthe table arranges in order Leaves the disease, some syndromes have the heredity, somewhathas located the specific gene flaw with the home position clonetechnology [ 8 ]. These syndromes are being sick the family members to beable to have the remarkable 表型 variation. This kind of situationand in 纯合子 is invalid The sudden change mouse sees the variation is similar, namelythe kidney finally 表型 is decided by the experimental mouse's genebackground. The kidney maldevelopment occurrence is several kind of differentgenes flaws, perhaps meets in the embryo development period sends 畸the factor And so on many kinds of genes regulation barrier finaloutcome. 肾间 the nature - epidermis transforms process as well asureter branch and growth Is complex and the huge gene system guides by, some genes arethe kidney specificity, some rights and wrongs are special . Certain growth factor genes, although they have the timeexpression in the kidney to be active, but when they are destroyedcertainly not shade The loud kidney normal growth, this meant the growth kidneynormal expression each kind of gene has in the function overlaps [ 9]. Another one Plants the possibility is this kind of normal expression formdestruction in the kidney maldevelopment occurrence development thecertain function, or Is the kidney maldevelopment cause. The latter 肾间 nature flaw may cause the kidney , the gene ill should is the dislocation expression, possiblyto kidney The maldevelopment plays the certain role. On clinical hasthe isolation the multi- pouches kidney maldevelopment and theobstruction kidney maldevelopment two Parallel existence case of illness. Congenitalness and theexperimental nature single gene mutation may cause the pouch kidneygrowth to be unusual, these genes The sudden change may change mutually relates. Theoreticallyspeaking, the sudden change may affect: (1) 胚基 proliferation andsplit up ureter drive pipe minute An institute must peptide and matrix protein expression; (2)Ureter drive pipe to after kidney 胚基 signal reaction capacity; (3)Loses After the ureter drive pipe expression starts and maintainsthe kidney 胚基 epidermis induction to need the protein the ability;(4) Latter kidney 胚基 to these letters The number carries on the response the ability; (5) Ureterbud and latter kidney 胚基 cell to signal reaction capacity [ 10 ]. Recently already separated the phosphoric acid glucose phaseomanniteglycoprotein gene, was called the GPC3 gene. The GPC3 flaw and aremany Pouch kidney maldevelopment related [ 11 ]. Although thesingle gene may finally cause the kidney maldevelopment with themulti- genes flaw, but Its 表型 possibly decided to receives the gene regulationwhich affects to be out of balance or the expression change at first,like congenital obstruction and pouch Kidney maldevelopment [ 12, 13 ]. The multi- pouchesmaldevelopment kidney, and in the nature has the growth factor gene inthe pouch epidermis Change. In the mouse obstruction growth kidney, the bloodvessel tense element and the shift growth factor assumes excessivelyexpresses [ 14 ]. Grinds Investigates the proof, in the after kidney growth unusualarea, promotes the acorn tube epidermis to appear the pouch changefactor Pax2 and Bcl-2 same Assumes excessively expresses [ 15, 16 ]. This researchpossibly can provide the important line to each kind of form kidneymaldevelopment pathogenesis Rope. 先天性肾发育不良与分子生物学的研究 摘要 肾发育不良是肾发生异常的临床后果，其典型病理组织学特征是出现原始肾小球和肾小管、软骨样化生等。近年来通过应用靶基因和原位克隆等分子技术对正常哺乳动物肾脏发生分子调控机制的研究，对先天性肾发育不良的发病机理有了更多的了解。本文将对先天性肾发育不良的分子生物学研究近况作一讨论，并对包括生长因子在内的几种基因突变、转录调控障碍及表达变化与肾发良不良的关系进行探讨。 肾发育不良是肾脏未能进行正常生长发育形成的先天性疾病，过去对其发病机理了解甚少，随着分子生物技术的发展和应用，从分子学机理来阐明肾脏的发生，从分子生物学水平对肾发育不良的发生有了较深入的认识。本文就近期对此问题的研究进展作一介绍。1 肾发生与肾发育不良 正常哺乳类肾脏位于间介中胚层，中胚层分化形成前肾导管，经进一步诱导形成中肾导管至输尿管芽，在输尿管芽诱导下，胚体尾端两侧的生肾素分化为后肾胚基，肾脏的胚胎发育正是由输尿管芽和后肾胚基二部分完成的，前者逐步发育成肾盂、肾盏和集合管，后者发育成肾小管和肾小球，最后肾小管和集合管对接，构成正常的肾单位。如果输尿管芽和后肾胚基二部分不能按正常程度发育和实行对接即造成肾发育不良。肾发育不良可以是部分性的，也可以是完全性的。多数类型的肾发育不良伴有囊肿，提示发育不良的各种形式在形成中有共同机制。 临床上常见的先天性肾发育不良包括多囊性、梗阻性肾发育不良以及与基因有关的肾发育异常。病理组织学重要特征是出现原始肾小管和化生软骨。完全性单侧肾发育不良，可表现为无症状。多数发育不良病例中，肾缺陷是双侧性的，提示基因突变在正常肾发育中起重要作用。单侧性疾病则可能是一种获得性损伤所致，该损伤破坏了基因的正常表达，进而影响了对肾成熟有重要意义的蛋白质的产生。2 肾发育不良常见类型 先天多囊性肾发育不良 多囊性肾发育不良（multiple cystic hypoplastic）是一种常见的完全性肾发育不良，多为单侧病变（14-20%为双侧性），患肾失去正常形态，被不规则的大小囊肿所代替，肾脏功能丧失并常伴有输尿管梗阻，是新生儿腹部包块最常见的原因之一。 多囊性发育不良肾外型呈肾形结构，多数病例伴有一个闭锁的输尿管。妊娠早期的多囊肾含有正常发育所必须的成份，包括未诱导的后肾胚基岛和分支的输尿管导管，在此阶段肾单位各段已均可鉴别出囊性改变[1]。生后多囊性发育不良肾的病理组织学变异包括原始肾小管的囊性改变、膨大且结构破坏、具有明显管周围反应的间质、纤维肌环的形成、软骨成分为标志的组织转化等。 先天梗阻性肾发育不良 先天性尿路梗阻在解剖位置上常发生于输尿管和膀胱的连接处，先天性后尿道瓣膜是婴幼儿泌尿系统梗阻的重要原因。先天梗阻性肾的组织学特征与多囊性肾发育不良相似，包括肾单位各段如肾小球的囊性转化、间质膨大且结构破坏、髓质和直小血管显著发育不全、发生管周围纤维肌环、多种形式的肾小球和发育的肾单位各段。与多囊性肾发育不良一样，先天梗阻性肾表现为一系列疾病，其程度与胚胎期尿流阻塞发生的时间有关[2]。表 伴有肾发育异常的综合症------------------------------------------------------综合症 染色体遗传形式------------------------------------------------------尖头并指（趾）畸形（Apert’s） 常染色体显性 致窒息的胸廓营养不良 常染色体隐性 肥胖、生殖机能减退等 常染色体隐性 鳃-耳-肾 常染色体显性 Campomelic发育异常 常染色体隐性 脑-肝-肾（Passarge’s） 常染色体隐性 Fryns’s 常染色体隐性 Goemine’s X-连接的 Goldston(遗传性毛细血管扩张) 常染色体隐性？ Hall-Pallster’s 散发的 Ivemark’s 常染色体隐性 Marden-Walker’s 常染色体隐性 Mecket-Gruber 常染色体隐性 Miranda’s 常染色体隐性 Senlor-Loken’s 常染色体隐性？ 三体染色体16-18（Edwards） 三体染色体13-15（Patau） 三体染色体21（Down） 结节性硬化 常染色体显性 Von Hippel-Lindau 常染色体显性------------------------------------------------------ 肾发育不良综合症 肾发育不良综合症是包括囊性发育不良等肾畸形在内的遗传性征候群（见表）。现阐明一部分综合症其特异的基因和蛋白质缺陷。发育不良表现型的外显率呈现一个谱带，提示有其他基因影响肾的最终表型。发育不良通常都包含多种器官，说明缺陷的基因涉及正常器官发生的基础。病理组织学发现，此类综合症轻者可能出现巨囊形成（如结节性硬化），重者可能出现囊性发育异常和肾衰竭（Meckel-Gruber综合症）。3 肾发育不良分子生物学 目前的研究发现有多种基因与肾发育不良有关，如WT-1、Pax-2、GDNF、BF-2、BMP-7、PDGF、Wnt-4等基因在后肾胚基表达。Pax-2、c-ret、BMP-7、α3β1等在输尿管芽表达。当这些基因缺乏或被破坏时，肾脏不能正常地发生与发育[3]。Sonnenberg等[4]用特异性抗体与放射标记的补体RNA和DNA探针进行研究，确定了多肽生长因子、肝素结构生长因子及它们的受体、细胞外基质分子和细胞表面整合素等基因在肾发育中的特定表达位置。例如肝细胞生长因子主要在后肾胚基因内表达，而其受体c-met则在输尿管胚芽上皮表达。这种多肽及其受体在两种类型细胞上的表达说明输尿管导管对后肾间质的形成起诱导作用。Schuchardt等[5]通过应用基因重组与制备纯合子无效突变小鼠，发现一些影响肾发育的基因和多肽，如转移生长因子-β、肝细胞生长因子、胰岛素样生长因子-Ⅱ，根据所见到的最终表型推断特定基因在正常肾发生中的作用。酪氨酸激酶体受体c-ret在分支输尿管导管以及配体-神经胶质衍生的神经营养因子上表达。当小鼠c-ret基因被破坏时，导致全肾发育不良。转录因子基因编码蛋白能与DNA结合，而且具备调控其它基因表达的功能。在哺乳动物肾发育中，Wilms’肿瘤基因WT-1及Pax2均编码转录因子，其表达形式影响肾细胞的分化[6，7]。基因性综合症与肾形成异常有关，表中所列出的疾病，有些综合症有遗传性，有些用原位克隆技术已定位出特定的基因缺陷[8]。这些综合症在患病家族成员能发生显著的表型变异。这种情况与在纯合子无效突变小鼠所见的变异相似，即肾的最终表型取决于实验小鼠的基因背景。 肾发育不良的发生是几种不同的基因缺陷，或是在胚胎发育期遇到致畸因子等多种基因调控障碍的最终结果。肾间质-上皮转化的过程以及输尿管分支和生长，是由一个复杂而庞大的基因体系来导向，有些基因是肾特异性的，有些是非特异的。某些生长因子基因，尽管它们在肾发生期表达活跃，但当它们被破坏时并不影响肾的正常发育，这意味着发育肾正常表达的各种基因在功能上有重叠[9]。另一种可能性是这种正常表达形式的破坏在肾发育不良的发生发展中起一定作用，或者就是肾发育不良的起因。 后肾间质缺陷可导致肾发育不良。另外，基因不适应和错位表达，可能对肾发育不良起一定作用。临床上有孤立的多囊性肾发育不良和梗阻性肾发育不良两者并行存在的病例。先天性和实验性单基因突变均可导致囊性肾发育异常，这些基因突变可改变相互联系。从理论上讲，突变可影响：①胚基增生和分化输尿管导管分支所必需的肽和基质蛋白的表达；②输尿管导管对后肾胚基信号的反应能力；③输尿管导管表达启动和维持后肾胚基上皮诱导所需蛋白的能力；④后肾胚基对这些信号进行反应的能力；⑤输尿管芽和后肾胚基细胞对信号的反应能力[10]。 最近已经分离出磷酸葡萄糖肌醇糖蛋白基因，简称GPC3基因。GPC3缺失与多囊性肾发育不良有关[11]。虽然单基因与多基因缺陷均可最终导致肾发育不良，但其表型可能决定于最初受影响的基因调控失调或表达改变，如先天性梗阻性和囊性肾发育不良[12，13]。多囊性发育不良肾，在囊性上皮和间质中均有生长因子基因的改变。在小鼠梗阻性发育肾中，血管紧张素和转移生长因子呈过度表达[14]。研究证明，在后肾发育异常区，促进小管上皮出现囊性改变的因子Pax2和Bcl-2同样呈过度表达[15，16]。此研究可能会对各种形式肾发育不良的发病机制提供重要线索。