全 文 ：第25卷 第9期
2013年9月
生命科学
Chinese Bulletin of Life Sciences
Vol. 25, No. 9
Sep., 2013
文章编号：1004-0374(2013)09-0878-08
收稿日期：2013-04-02；修回日期：2013-06-21
基金项目：浙江省自然科学基金项目(LQ13H120004)
*通信作者：E-mail: xyma1985@gmail.com
RPE细胞的正常功能及其在眼科疾病中的作用
王海青1，牛国桢2，张晓波2，麻晓银2*
(1 温州医科大学附属第一医院生殖中心，温州 325035； 2 温州医科大学附属眼视光医院, 温州 325035)
摘　要： 视网膜色素上皮 (retinal pigment epithelium, RPE)细胞在眼的发育和视觉功能中起着重要的作用，
具有分泌生长因子、抗氧化、参与视循环代谢、维持血 -视网膜屏障和吞噬视细胞脱落的外节盘膜等重要
生理功能。RPE细胞的正常结构和功能为视网膜感光细胞的正常发育及功能发挥所必需，若 RPE细胞出现
结构或功能异常则会导致视网膜感光细胞功能受损、视网膜退化等疾病。鉴于其重要性，就 RPE细胞的发育、
正常结构和功能进行综述，为其相关眼科疾病的治疗提供一定的依据。
关键词：视网膜病变；RPE；色素细胞；眼科
中图分类号：Q436；R774　　 文献标志码：A
The normal functions of RPE cell and its roles in eye disease
WANG Hai-Qing1, NIU Guo-Zhen2, ZHANG Xiao-Bo2, MA Xiao-Yin2*
(1 Reproductive Center, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China; 2 Eye
Hospital, Wenzhou Medical University, Wenzhou 325035, China)
Abstract: The retinal pigment epithelium (RPE) cells play important roles in eye development and visual functions.
RPE cells have the functions of secreting growth factor, antioxidant, involving in metabolism of visual cycle,
maintaining the blood-retinal barrier, phagocytosis of detached photoreceptor outer segments and other
physiological functions. RPE normality is essential for photoreceptor development and normal functions, and
defects in RPE cell structure or functions will cause photoreceptor dysfunction and retinal degeneration. Recent
studies have revealed new insights into important roles of RPE cells in related eye diseases. In this viewpoint, we
provide an overview of some of the current understanding of RPE normal structure and functions and their roles in
the development of related eye diseases.
Key words: retinal degeneration; RPE; pigment cell; eye disease
视网膜色素上皮 (retinal pigment epithelium, RPE)
由胚胎视泡发育而来，位于视网膜神经上皮层和脉
络膜之间 [1]，具有多种复杂的生理生化功能，与眼
的正常发育及部分眼科疾病的发生密切相关。RPE
细胞在眼内发挥作用时需要具备如下功能：屏障功
能、吞噬功能、参与视循环代谢、抗氧化功能和分
泌生长因子等 [2]。
RPE细胞在眼的正常发育、视网膜正常结构的
维持和功能发挥中起着重要的作用，并且在多种眼
科疾病中扮演重要的角色，因此，学者们对其结构
和功能开展了大量的工作，也得到了不少创新性的
发现。在此，将从以下八个方面对 RPE的结构和
功能进行论述。
1　RPE细胞的正常发育及其调控
在脊椎动物中，RPE细胞由视泡发育分化而来。
胚胎发育过程中，早期视泡细胞具有双向发育潜能，
可发育为视网膜神经上皮层或 RPE层 [3]。这种双向
潜能性与早期两个潜在区域所存在的基因调控有
关。转录因子MITF (microphthalmia-associated tran-
scription factor) 被证实参与了 RPE细胞的正常发育
王海青，等：RPE细胞的正常功能及其在眼科疾病中的作用第9期 879
分化过程，早期视泡都表达MITF，而在视杯阶段，
视网膜神经上皮层不再表达MITF，而 RPE层则继
续表达 MITF[4]。若 MITF功能异常，可引起 RPE
转分化为视网膜神经上皮细胞 [5]，Mitf基因敲除或
突变小鼠由于 RPE细胞不能正常发育，继而引起
神经视网膜退行性病变和小眼畸形等 (图 1)。反之，
外源性MITF的表达能诱导视网膜神经上皮细胞转
分化成为 RPE样细胞。
研究还证实其他转录因子或者信号通路分子同
样参与了 RPE细胞的正常发育分化的调控，如生
长因子 FGF1 (fibroblast growth factor 1)和 FGF2可
以上调转录因子 Chx10 (ceh-10 homeo domain con-
taining homolog) 的表达，而 Chx10 则可以抑制
MITF的表达，从而调控早期视泡细胞向神经视网
膜发育分化 [8]。
通过基因敲除或基因突变小鼠研究还发现转录
因子 OTX1 (orthodenticle homeobox 1) 和 OTX2 以
及 Pax2 (paired box 2)和 Pax6也参与调控 RPE细胞
的正常发育。Otx1-/-；Otx2+/-小鼠眼中呈现不同程
度的 RPE细胞向神经视网膜细胞转分化现象 [9]。
Pax2-/-；Pax6+/-小鼠 RPE细胞则呈现 Mitf-/-小鼠样
变化，小鼠胚胎发育过程中所有视泡区域不表达
MITF，而表达神经视网膜细胞的标记分子。反之，
如果利用转基因手段在视柄区域异位表达转录因子
Pax6，则可以诱导MITF的表达，使视柄区域分化
形成 RPE样细胞 [10]。
由此可见，RPE细胞的正常发育是一个由转录
因子、信号通路等复杂的细胞内网络途径所共同调
控的发育生物学事件，RPE细胞的正常发育与否直
接影响眼的正常发育，与视网膜的正常结构和功能
以及视觉功能的形成密切相关。
2　RPE细胞的正常结构
RPE位于视网膜神经上皮层和脉络膜之间，排
A：Mitfmi-vga9/Mitfmi-vga9为Mitf基因敲除小鼠，该小鼠表现为全身白色和小眼畸形。B：Mitfmi/Mitfmi为Mitf基因功能区域发生一个
3 bp碱基的缺失，该小鼠同样表现为白色和小眼畸形。C：Mitfmi-rw/Mitfmi-rw小鼠在Mitf基因启动子区域发生了一段大的缺失，
该小鼠一只眼睛表现为小眼畸形，另一只眼睛大小正常，但是色素缺失。D：MitfMi-b/MitfMi-b小鼠MITF发生了一个G244E的点
突变，该小鼠眼睛大小正常，但是色素缺失并且视网膜呈现退行性病变[6-7]。
图1 不同Mitf等位基因突变小鼠呈现不同程度的眼异常状态
生命科学 第25卷880
列整齐，具有单层六边形结构 [11]。RPE细胞表面可
向视锥视杆细胞层伸出微绒毛，这些微绒毛可以促
进 RPE细胞与神经视网膜层细胞之间的连接和物
质转运 [12]。RPE细胞的侧膜之间是紧密的连接复合
体结构，其基底膜则是一个复杂的内折状结构。
RPE细胞的这些结构为其极性的形成和屏障功能的
发挥以及物质的运输起着关键性的作用 [13-16]。RPE
细胞的这一生理功能异常被认为与相关眼科疾病的
发生密切相关，如 RPE细胞屏障功能异常则易导
致 Best卵黄样黄斑营养不良 (Best vitelliform macular
dystrophy, BVMD)[17]和成人卵黄样黄斑营养不良
(adult-onset vite-lliform macular dystrophy, AVMD)[18]。
RPE基底膜与 Bruchs membrane之间的连接或功
能异常被认为与年龄相关性黄斑变性 (age-related
macular degeneration，AMD)[19-20]和 Sorsbys眼底营
养不良 [21]的发生相关。
RPE细胞的另一生理特点是其含有色素。鉴于
眼结构的特殊性和正常的生理需要，神经视网膜是
体内一类经常性暴露在光照下的神经组织，而与之
相邻的 RPE细胞层会为神经视网膜吸收和过滤光
线。为了发挥此项功能，RPE细胞具有吸收不同波
长光线能力的色素。在 RPE细胞中存在黑色素和
脂褐素，它们可以吸收不同波长的光源，进而保护
神经视网膜 [22-24]。RPE细胞中的黑色素小体与细胞
的抗氧化能力相关，实验证实其参与了细胞清除氧
自由基的生理过程，并具有螯合细胞内金属离子的
能力 [25]。如果人眼内色素水平异常，则会引起一系
列的眼科疾病，如视神经异常、眼球震颤、视力减退、
夜盲等等 [26]。
3　RPE细胞的分泌功能
RPE细胞的重要生理功能之一是通过分泌生长
因子来影响神经视网膜细胞及其自身的生理特性，
这其中包括为视网膜感光细胞提供营养、促进感光
细胞的存活和维持视网膜的结构完整性等 [3, 27-28]。
RPE细胞能够合成、分泌多种生长因子，有的参与
RPE细胞自身的功能调节，有的则与某些眼科疾病
的发生相关 [29-30]，如研究发现，在 AMD、增殖性
糖尿病视网膜病变 (proliferative diabetic retinopathy，
PDR)和青光眼的患者眼中 PEDF的水平显著下降，
VEGF的异常高表达也被证实与 PDR等眼科疾病的
发生相关 [31-39]。利用 PEDF缺陷性小鼠研究发现，该
小鼠更为容易导致视网膜血管扩张和新生血管生成 [40]。
除了分泌生长因子，RPE细胞还可以分泌其他
物质，如红细胞生成素 (erythropoietin, EPO)。研究
证实，EPO及其受体 EPOR表达于 RPE细胞，并
且具有增强细胞的抗氧化损伤、抗细胞凋亡能力，
以及促进细胞生存、增殖的能力。研究提示 EPO的
表达异常可能与 PDR及 AMD等眼科疾病的发生密
切相关 [41-45]。
4　RPE细胞的抗氧化功能
由于光氧化等生理作用的存在，使得 RPE细
胞长期存在于一种高氧自由基的环境中，所以，
RPE细胞的一个重要功能就是抗氧化性，消除氧自
由基。目前的研究已经发现 RPE细胞中存在着高
含量的抗氧化酶，如 SOD (superoxide dismutase)和
Catalase[46-47]；此外还有一系列的非酶类物质，如类
胡萝卜素物质、谷胱甘肽和色素等物质 [23-24]。PDR
和 AMD等眼科疾病通常被认为与 RPE细胞的抗氧
化功能下降有关 [48-50]。
目前对于 RPE细胞抗氧化能力的研究已有不
少报道。2006年，Glotin等 [51]研究发现，ERK信
号通路参与了RPE细胞抗氧化能力的调控；2007年，
Alcazar等 [52]研究证实功能基因MMP-14和 TIMP-2
能加强 RPE细胞的抗氧化能力；2011年，Lin等 [53]
研究报道 miR-23在 RPE细胞的氧化损伤中起调控
作用；2013年，Patel和 Hackam[54]研究表明，Toll-
like receptor 3 (TLR3)具有保护 RPE细胞氧化损伤
的功能。由此可见，RPE细胞抗氧化功能同样是一
个受细胞内复杂的信号网络共同调控而实现的重要
的细胞生物学事件。
5　RPE细胞的吞噬功能与屏障功能
RPE对光感受器外节脱落细胞碎片的吞噬消化
对于维持视网膜正常生理结构与功能具有重要作
用 [55-56]。在病程较长的糖尿病患者中，发现其 RPE
吞噬功能呈现异常状态，继而伴随糖尿病性视网膜
疾病的发生 [57]。通过研究，目前已经证实有多种
RPE细胞膜受体参与了 RPE细胞的吞噬功能调节，
如 IGF2R (insulin-like growth factor 2 receptor)[58]、
CD36 (thrombospondin receptor)[59-60]、αVβ5 integrin[61]
以及其他的功能基因，如MERTK(c-mer proto-onco-
gene tyrosine kinase)[62]、ARMS2 (age-related maculo-
pathy susceptibility 2)[63]。如果这些基因突变或功能
异常，影响 RPE细胞的正常吞噬功能，则可引起不
同程度的眼科疾病，如MERTK基因突变可导致视网
膜营养不良和遗传性视网膜变性等眼科疾病 [64-65]。
王海青，等：RPE细胞的正常功能及其在眼科疾病中的作用第9期 881
RPE细胞在视网膜中起重要的屏障作用，是血 -
视网膜屏障的重要组成部分 [66-70]，在脉络膜和视网
膜细胞之间的营养物质、水、电解质等的转运中起
着非常关键的作用。RPE细胞可从血液中吸收葡萄
糖、视黄醇等营养物质并将其转运至视网膜感光细
胞。同时，RPE细胞的屏障功能还具有维持视网膜
Na+-K+平衡等生理功能。研究证实，多种细胞分子
参与了对 RPE细胞屏障功能的调控，如 GLUT1
(glucose transporter 1)和 GLUT3可以调控葡萄糖的
转运 [71-73]，NPD1 (neuroprotectin D1)参与了 RPE细
胞中 DHA的运输 [74-75]。这些基因发生突变或者功
能异常将可导致相关的眼科异常，如研究发现
Glut1基因敲除小鼠表现为眼血管生成异常 [76]。
6　RPE细胞的视循环功能
眼因为视循环的存在而能够看得见物体，而视
循环是一个复杂的细胞内代谢过程。研究已证实，
RPE细胞中的关键基因，如 RPE65[77-78]、IRBP (inter-
photoreceptor retinol binding protein)[79-80]、RDH
(retinol dehydrogenases)[81-82]、LRAT (lecithin:retinol
acyl transferase)[83]、CRALBP (cellular retinaldehyde
binding protein)[84]、RGR (RPE-retinal G protein
receptor)[85]等基因参与了视循环代谢并起重要的作
用。如果视循环功能异常或视循环通路中相关基因
突变可导致相关眼科疾病的发生，如 RPE65或 LRAT
基因突变可导致 Leber氏先天性黑蒙 (leber conge-
nital amaurosis)[86-88]，RDH5 和 CRALBP 基因突变
或功能异常可导致视网膜营养性萎缩 [89-91]。
7　RPE细胞的增殖和迁移
在正常情况下，成熟的 RPE细胞在体内是一
种单层的，处于相对静止状态的细胞。但是在某些
病理状态下，如在 PVR (proliferative vitreoretino-
pathy, 增生性玻璃体视网膜病变 )、视网膜脱离患者
中，RPE细胞可发生异常的增殖与迁移，进而导致
患者的视力受损 [92]。目前 RPE细胞异常增殖相关
的眼科疾病在发达国家尤其是在视网膜手术患者人
群中发病率较高，也越来越受到学者的关注。研究
证实，RPE细胞层与神经视网膜层脱离之后，RPE
细胞可进入玻璃体腔，发生上皮间质细胞转化
(epithelial-mesenchymal transitions, EMT)之后开始
异常增殖 [93-94]。不少学者对 RPE细胞增殖调控中
的分子机制进行了研究。2007年，Li等 [92]在细胞
生物学水平研究证实了生长因子 PDGF可以影响
RPE细胞的增殖。2009年，Liu等 [95]利用 siRNA
技术和 Zeb1+/-小鼠研究发现，Zeb1可以调控转录
因子MITF的表达进而影响 RPE细胞的增殖调控。
2009年，Tsukiji等 [96]在鸡胚 RPE细胞中研究发现
如果在 RPE细胞中过表达显性负性的MITF突变体
则可以显著地提高 RPE细胞的增殖率。2010年，
Schouwey等 [97]利用转基因小鼠证实 Notch信号通
路可以影响 RPE细胞的增殖。关于 MITF在 RPE
细胞中的生物学功能，本课题组也开展了相关的研
究，实验结果提示，MITF通过调控生长因子 PEDF
的表达，进而抑制 RPE细胞的迁移 [98]。由此可见，
RPE细胞增殖与迁移的调控机制是一个由多种转录
因子、信号通路和生长因子共同参与调控的复杂的
过程。
8　RPE细胞与高度近视
高度近视是指近视度数在 -6D以上，眼轴长度
大于等于 26 mm的屈光不正性眼科疾病。该类疾病
的发病率呈逐年增加趋势，严重者可导致失明。基
于最新的研究结果，RPE细胞还被认为可能与高度
近视的发生相关。在 RPE细胞色素缺失的白化患
者群中，高度近视的比率显著高于正常人群 [99]。
2011年，Shi等 [100]通过外显子测序研究发现，
ZNF644 (zinc finger protein 644 isoform 1)基因突变
与高度近视的发生存在相关性。通过后续实验，他
们证实了 ZNF644表达于 RPE细胞中，并提示可能
在RPE细胞中调控其他基因的表达。此外，Shi等 [101]
还采用 GWAS (genome-wide association study)技术
研究发现，人类染色体 13q12.12区域多态性可能
与高度近视的发生相关。通过后续分析，他们明确
了这段区域包含 MIPEP (mitochondrial intermediate
peptidase)、C1QTNF9B-AS1 和 C1QTNF9B (C1q and
tumor necrosis factor related protein 9B) 三个基因，
同时，他们进一步明确了MIPEP和 C1QTNF9B在
RPE细胞中表达。这些研究结果提示了 RPE细胞
中相关基因的表达或者功能异常可能与高度近视的
发生相关。但是，这一科学结论还有待于后续更多
的实验数据予以支持并证明。
9　小结
目前的研究证实，RPE是一种具有重要功能且
与多种眼科疾病密切相关的色素细胞。RPE细胞的
结构或者功能异常可引起视网膜病变、视觉功能异
常，严重者可致盲。但是，对 RPE细胞的生物学
生命科学 第25卷882
功能及其调控机制尚不完全清楚。有望通过继续深
入进行相关方面的研究，全面认识 RPE细胞的功
能及其调控机制，为最终克服 RPE细胞相关的眼
科疾病起积极的推动作用。
致 谢：感谢温州医科大学侯陵教授对本文做了细致
的修改和指导。
[参　考　文　献]
Marks MS, Seabra MC. The melanosome: membrane [1]
dynamics in black and white. Nat Rev Mol Cell Biol,
2001, 2(10): 738-48
Simó R, Villarroel M, Corraliza L, et al. The retinal [2]
pigment epithelium: something more than a constituent of
the blood-retinal barrier--implications for the pathogenesis
of diabetic retinopathy. J Biomed Biotechnol, 2010, 2010:
190724
Chow RL, Lang RA. Early eye development in [3]
vertebrates. Annu Rev Cell Dev Biol, 2001, 17: 255-96
Nguyen M, Arnheiter H. Signaling and transcriptional [4]
regulation in early mammalian eye development: a link
between FGF and MITF. Development, 2000, 127(16):
3581-91
Bumsted KM, Barnstable CJ. Dorsal retinal pigment [5]
epithelium differentiates as neural retina in the
microphthalmia (mi/mi) mouse. Invest Ophthalmol Vis
Sci, 2000, 41(3): 903-8
Steingrímsson E, Arnheiter H, Hallsson JH, et al. [6]
Interallelic complementation at the mouse Mitf locus.
Genetics, 2003, 163(1): 267-76
Hou L, Pavan WJ. Transcriptional and signaling regulation [7]
in neural crest stem cell-derived melanocyte development:
do all roads lead to Mitf? Cell Res, 2008, 18(12): 1163-76
Horsford DJ, Nguyen MT, Sellar GC, et al. [8] Chx10
repression of Mitf is required for the maintenance of
mammalian neuroretinal identity. Development, 2005,
132(1) :177-87
Martinez-Morales JR, Signore M, Acampora D, et al. [9] Otx
genes are required for tissue specification in the
developing eye. Development, 2001, 128(11): 2019-30
Bäumer N, Marquardt T, Stoykova A, et al. Retinal [10]
pigmented epithelium determination requires the
redundant activities of Pax2 and Pax6. Development,
2003, 130(13): 2903-15
Bok D, Hall MO. The role of the pigment epithelium in [11]
the etiology of inherited retinal dystrophy in the rat. J Cell
Biol, 1971, 49(3): 664-82
Miller SS, Steinberg RH. Passive ionic properties of frog [12]
retinal pigment epithelium. J Membr Biol, 1977, 36(4):
337-72
Shin K, Fogg VC, Margolis B. Tight junctions and cell [13]
polarity. Ann Rev Cell Dev Biol, 2006, 22: 207-35
Rizzolo LJ. Development and role of tight junctions in the [14]
retinal pigment epithelium. Int Rev Cytol, 2007, 258:195-
234
Hu J, Bok D. A cell culture medium that supports the [15]
differentiation of human retinal pigment epithelium into
functionally polarized monolayers. Mol Vis, 2001, 7: 14-9
Konrad M, Schaller A, Seelow D, et al. Mutations in the [16]
tight-junction gene claudin 19 (CLDN19) are associated
with renal magnesium wasting, renal failure, and severe
ocular involvement. Am J Hum Genet, 2006, 79(5): 949-
57
Zhang Y, Stanton JB, Wu J, et al. Suppression of Ca[17] 2+
signaling in a mouse model of best disease. Hum Mol
Genet, 2010, 19(6): 1108-18
Saito W, Yamamoto S, Hayashi M, et al. Morphological [18]
and functional analyses of adult onset vitelliform macular
dystrophy. Br J Ophthalmol, 2003, 87(6): 758-62
Davis MD, Gangnon RE, Lee LY, et al. The Age-Related [19]
Eye Disease Study severity scale for age-related macular
degeneration: AREDS Report No. 17. Arch Ophthalmol,
2005, 123(11): 1484-98
Yates JR, Sepp T, Matharu BK, et al. Complement C3 [20]
variant and the risk of age-related macular degeneration.
N Engl J Med, 2007, 357(6): 553-61
Fariss RN, Apte SS, Luthert PJ, et al. Accumulation of [21]
tissue inhibitor of metalloproteinases-3 in human eyes
with Sorsbys fundus dystrophy or retinitis pigmentosa. Br
J Ophthalmol, 1998, 82(11): 1329-34
Beatty S, Boulton M, Henson D, et al. Macular pigment [22]
and age related macular degeneration. Br J Ophthalmol,
1999, 83(7): 867-77
Beatty S, Koh HH, Phil M, et al. The role of oxidative [23]
stress in the pathogenesis of age-related macular
degeneration. Surv Ophthalmol, 2000, 45(2): 115-34
Beatty S, Murray IJ, Henson DB, et al. Macular pigment [24]
and risk for age-related macular degeneration in subjects
from a northern European population. Invest Ophthalmol
Vis Sci, 2001, 42(2): 439-46
Kaczara P, Zaręba M, Herrnreiter A, et al. Melanosome-[25]
iron interactions within retinal pigment epithelium-derived
cells. Pigment Cell Melanoma Res, 2012, 25(6): 804-14
Lund RD. Uncrossed visual pathways of hooded and [26]
albino rats. Science, 1965, 149(3691): 1506-7
Becerra SP. Focus on molecules: pigment epithelium-[27]
derived factor (PEDF). Exp Eye Res, 2006, 82(5):7 39-40
Tombran-Tink J, Shivaram SM, Chader GJ, et al. [28]
Expression, secretion, and age-related downregulation of
pigment epithelium-derived factor, a serpin with
neurotrophic activity. J Neurosci, 1995, 15 (7 Pt 1): 4992-
5003
Ablonczy Z, Prakasam A, Fant J, et al. Pigment [29]
epithelium-derived factor maintains retinal pigment
epithelium function by inhibiting vascular endothelial
growth factor-R2 signaling through γ-secretase. J Biol
Chem, 2009, 284(44): 30177-86
He S, Kumar SR, Zhou P, et al. Soluble EphB4 inhibition [30]
of PDGF-induced RPE migration in vitro . Invest
Ophthalmol Vis Sci, 2010, 51(1): 543-52
Matsunaga N, Chikaraishi Y, Izuta H, et al. Role of soluble [31]
王海青，等：RPE细胞的正常功能及其在眼科疾病中的作用第9期 883
vascular endothelial growth factor receptor-1 in the
vitreous in proliferative diabetic retinopathy. Ophthal-
mology, 2008, 115(11): 1916-22
Murugeswar i P, Shukla D, Rajendran A, e t a l . [32]
Proinflammatory cytokines and angiogenic and anti-
angiogenic factors in vitreous of patients with proliferative
diabetic retinopathy and eales disease. Retina, 2008,
28(6): 817-24
Binder S, Stanzel BV, Krebs I, et al. Transplantation of the [33]
RPE in AMD. Prog Retin Eye Res, 2007, 26(5): 516-54
Mangan BG, Al-Yahya K, Chen CT, et al. Retinal pigment [34]
epithelial damage, breakdown of the blood–retinal barrier,
and retinal inflammation in dogs with primary glaucoma.
Vet Ophthalmol, 2007, 10(Suppl. 1): 117-24
Ogata N, Matsuoka M, Imaizumi M, et al. Decreased [35]
levels of pigment epithelium-derived factor in eyes with
neuroretinal dystrophic diseases. Am J Ophthalmol, 2004,
137(6): 1129-30
Pons M, Marin-Castano ME. Cigarette smoke-related [36]
hydroquinone dysregulates MCP-1, VEGF and PEDF
expression in retinal pigment epithelium in vitro and in
vivo. PLoS One, 2011, 6(2):e 16722
Hiscott P, Gray R, Grierson I, et al. Cytokeratin-containing [37]
cells in proliferative diabetic retinopathy membranes. Br J
Ophthalmol, 1994, 78(3): 219-22
Gartner S, Henkind P. Pathology of retinitis pigmentosa. [38]
Ophthalmology, 1982, 89(12):1425-32
Schuman SG, Koreishi AF, Farsiu S, et al. Photoreceptor [39]
layer thinning over drusen in eyes with age-related
macular degeneration imaged in vivo with spectral-domain
optical coherence tomography. Ophthalmology, 2009,
116(3): 488-96
Huang Q, Wang S, Sorenson CM, et al. PEDF-deficient [40]
mice exhibit an enhanced rate of retinal vascular
expansion and are more sensitive to hyperoxia-mediated
vessel obliteration. Exp Eye Res, 2008, 87(3): 226-41
Hernández C, Fonollosa A, García-Ramírez M, et al. [41]
Erythropoietin is expressed in the human retina and it is
highly elevated in the vitreous fluid of patients with
diabetic macular edema. Diabetes Care, 2006, 29(9):
2028-33
García-Ramírez M, Hernández C, Simó R. Expression of [42]
erythropoietin and its receptor in the human retina:
acomparative study of diabetic and nondiabetic subjects,
Diabetes Care, 2008, 31(6): 1189-94
Wang ZY, Shen LJ, Tu L, et al. Erythropoietin protects [43]
retinal pigment epithelial cells from oxidative damage.
Free Radic Biol Med, 2009, 46(8): 1032-41
Kim KH, Oudit GY, Backx PH. Erythropoietin protects [44]
against doxorubicininduced cardiomyopathy via a PI3K-
dependent pathway. J Pharmacol Exp Ther, 2008, 324(1):
160-9
Wu Y, Shang Y, Sun S, et al. Antioxidant effect of [45]
erythropoietin on 1-methyl- 4-phenylpyridinium-induced
neurotoxicity in PC12 cells. Eur J Pharmacol, 2007,
564(1-3): 47-56
Miceli MV, Liles MR, Newsome DA. Evaluation of [46]
oxidative processes in human pigment epithelial cells
associated with retinal outer segment phagocytosis. Exp
Cell Res, 1994, 214(1): 242-9
Oliver PD, Newsome DA. Mitochondrial superoxide [47]
dismutase in mature and developing human retinal
pigment epithelium. Invest Ophthalmol Vis Sci, 1992,
33(6): 1909-18
Kanwar M, Chan PS, Kern TS, et al. Oxidative damage in [48]
the retinal mitochondria of diabetic mice: possible
protection by superoxide dismutase. Invest Ophthalmol
Vis Sci, 2007, 48(8): 3805-11
Madsen-Bouterse SA, Kowluru RA. Oxidative stress and [49]
diabetic retinopathy: pathophysiological mechanisms and
treatment perspectives. Rev Endocr Metab Disord, 2008
9(4): 315-27
Silva KC, Rosales MAB, Biswas SK, et al. Diabetic [50]
retinal neurodegeneration is associated with mitochondrial
oxidative stress and is improved by an angiotensin
receptor blocker in a model combining hypertension and
diabetes. Diabetes, 2009, 58(6): 1382-90.
Glotin AL, Calipel A, Brossas JY, et al. Sustained versus [51]
transient ERK1/2 signaling underlies the anti- and
proapoptotic effects of oxidative stress in human RPE
cells. Invest Ophthalmol Vis Sci, 2006, 47(10): 4614-23
Alcazar O, Cousins SW, Marin-Castaño ME. MMP-14 and [52]
TIMP-2 overexpression protects against hydroquinone-
induced oxidant injury in RPE: implications for
extracellular matrix turnover. Invest Ophthalmol Vis Sci,
2007, 48(12): 5662-70
Lin H, Qian J, Castillo AC, et al. Effect of miR-23 on [53]
oxidant-induced injury in human retinal pigment epithelial
cells. Invest Ophthalmol Vis Sci, 2011, 52(9): 6308-14
Patel AK, Hackam AS. Toll-like receptor 3 (TLR3) [54]
protects retinal pigmented epithelium (RPE) cells from
oxidative stress through a STAT3-dependent mechanism.
Mol Immunol, 2013, 54(2): 122-31
Bosch E, Horwitz J, Bok D. Phagocytosis of outer [55]
segments by retinal pigment epithelium: phagosome-
lysosome interaction. J Histochem Cytochem, 1993, 41(2):
253-63
Finnemann SC. Focal adhesion kinase signaling promotes [56]
phagocytosis of integrin-bound photoreceptors. EMBO J,
2003, 22(16): 4143-54
Liu BF, Miyata S, Kojima H, et al. Low phagocytic [57]
activity of resident peritoneal macrophages in diabetic
mice: relevance to the formation of advanced glycation
end products. Diabetes, 1999, 48(10): 2074-82
Tarnowski BI, Shepherd VL, McLaughlin BJ. Mannose [58]
6-phosphate receptors on the plasma membrane on rat
retinal pigment epithelial cells. Invest Ophthalmol Vis Sci,
1988, 29(2): 291-7
Ryeom SW, Silverstein RL, Scotto A, et al. Binding of [59]
anionic phospholipids to retinal pigment epithelium may
be mediated by the scavenger receptor CD36. J Biol
Chem, 1996, 271(34): 20536-9
Ryeom SW, Sparrow JR, Silverstein RL. CD36 participates [60]
in the phagocytosis of rod outer segments by retinal
生命科学 第25卷884
pigment epithelium. J Cell Sci, 1996, 109(Pt 2): 387-95
Lin H, Clegg D. Integrin αvβ5 participates in the binding [61]
of photoreceptor rod outer segments during phagocytosis
by cultured human retinal pigment epithelium. Invest
Ophthalmol Vis Sci, 1998, 39(9): 1703-12
DCruz PM, Yasumura D, Weir J, et al. Mutation of the [62]
receptor tyrosine kinase gene Mertk in the retinal
dystrophic RCS rat. Hum Mol Genet, 2000, 9(4): 645-51
Xu YT, Wang Y, Chen P, et al. Age-related maculopathy [63]
susceptibility 2 participates in the phagocytosis functions
of the retinal pigment epithelium. Int J Ophthalmol, 2012,
5(2): 125-32
Gal A, Li Y, Thompson DA, et al. Mutations in MERTK, [64]
the human orthologue of the RCS rat retinal dystrophy
gene, cause retinitis pigmentosa. Nat Genet, 2000, 26(3):
270-1
Thompson DA, McHenry CL, Li Y. Retinal dystrophy due [65]
to paternal isodisomy for chromosome 1 or chromosome
2, with homoallelism for mutations in RPE65 or MERTK,
respectively. Am J Hum Genet, 2002, 70(1): 224-9
Strauss O. The retinal pigment epithelium in visual [66]
function. Physiol Rev, 2005, 85(3):845-81
Ban Y, Rizzolo LJ. Differential regulation of tight junction [67]
permeability during development of the retinal pigment
epithelium. Am J Physiol Cell Physiol, 2000, 279(3):
C744-50
Erickson KK, Sundstrom JM, Antonetti DA. Vascular [68]
permeability in ocular disease and the role of tight
junctions. Angiogenesis, 2007, 10(2): 103-17
Villarroel M, García-Ramírez M, Corraliza L, et al. Effects [69]
of high glucose concentration on the barrier function and
the expression of tight junction proteins in human retinal
pigment epithelial cells. Exp Eye Res, 2009, 89(6): 913-
20
Rizzolo LJ. The distribution of Na[70] +,K+-ATPase in the
retinal pigmented epithelium from chicken embryo is
polarized in vivo but not in primary cell culture. Exp Eye
Res, 1990, 51(4): 43546
Ban Y, Rizzolo LJ. Regulation of glucose transporters [71]
during development of the retinal pigment epithelium.
Brain Res Dev Brain Res, 2000, 121(1): 89-95
Bergersen L, ohannsson EJ, Veruki ML, et al. Cellular and [72]
subcellular expression of monocarboxylate transporters in
the pigment epithelium and retina of the rat. Neuroscience,
1999, 90(1): 319-31
Senanayake P, Calabro A, Hu JG, et al. Glucose utilization [73]
by the retinal pigment epithelium: evidence for rapid
uptake and storage in glycogen, followed by glycogen
utilization. Exp Eye Res, 2006, 83(2): 235-46
Mukherjee PK, Marcheselli VL, Serhan CN, et al. [74]
Neuroprotectin D1: a docosahexaenoic acid-derived
docosatriene protects human retinal pigment epithelial
cells from oxidative stress. Proc Natl Acad Sci USA,
2004, 101(22): 8491-6
Bazan NG. Neurotrophins induce neuroprotective [75]
signaling in the retinal pigment epithelial cell by activating
the synthesis of the anti-inflammatory and anti-apoptotic
neuroprotectin d1. Adv Exp Med Biol, 2008, 613: 39-44
Zheng PP, Romme E, van der Spek PJ, et al., Defect of [76]
development of ocular vasculature in Glut1/SLC2A1
knockdown in vivo. Cell Cycle, 2011, 10(11): 1871-2
Hamel CP, Tsilou E, Pfeffer BA, et al. Molecular cloning [77]
and expression of RPE65, a novel retinal pigment
epithelium-specific microsomal protein that is post-
transcriptionally regulated in vitro. J Biol Chem, 1993,
268(21): 15751-7
Nicoletti A, Wong DJ, Kawase K, et al. Molecular [78]
characterization of the human gene encoding an abundant
61 kDa protein specific to the retinal pigment epithelium.
Hum Mol Genet, 1995, 4(4): 641-9
[79] Barrett DJ, Redmond TM, Wiggert B, et al. cDNA [79]
clones encoding bovine interphotoreceptor retinoid
binding protein. Biochem Biophys Res Commun, 1985,
131(3): 1086-93
Fong SL, Liou GI, Landers RA, et al. Purification and [80]
characterization of a retinol-binding glycoprotein
synthesized and secreted by bovine neural retina. J Biol
Chem, 1984, 259(10): 6534-42
Haeseleer F, Jang GF, Imanishi Y, et al. Dual-substrate [81]
specificity short chain retinol dehydrogenases from the
vertebrate retina. J Biol Chem, 2002, 277(47): 45537-46
Rattner A, Smallwood PM, Nathans J. Identification and [82]
characterization of all-transretinol dehydrogenase from
photoreceptor outer segments, the visual cycle enzyme
that reduces all-trans-retinal to all-trans-retinol. J Biol
Chem, 2000, 275(15): 11034-43
Ruiz A, Winston A, Lim YH, et al. Molecular and [83]
biochemical characterization of lecithin retinol acyltrans-
ferase. J Biol Chem, 1999, 274(6): 3834-41
Bunt-Milam AH, Saari JC. Immunocytochemical [84]
localization of two retinoid-binding proteins in vertebrate
retina. J Cell Biol, 1983, 97(3): 703-12
Hao W, Fong HK. Blue and ultraviolet light-absorbing [85]
opsin from the retinal pigment epithelium. Biochemistry,
1996, 35(20): 6251-6
Marlhens F, Bareil C, Griffoin JM, et al. Mutations in [86]
RPE65 cause Lebers congenital amaurosis. Nat Genet,
1997, 17(2): 139-41
Gu SM, Thompson DA, Srikumari CR, et al. Mutations in [87]
RPE65 cause autosomal recessive childhood-onset severe
retinal dystrophy. Nat Genet, 1997, 17(2): 194-7
Thompson DA, Li Y, McHenry CL, et al. Mutations in the [88]
gene encoding lecithin retinol acyltransferase are
associated with early-onset severe retinal dystrophy. Nat
Genet, 2001, 28(2): 123-4
Maw MA, Kennedy B, Knight A, et al. Mutation of the [89]
gene encoding cellular retinaldehyde-binding protein in
autosomal recessive retinitis pigmentosa. Nat Genet, 1997,
17(2): 198-200
Burstedt MS, Sandgren O, Holmgren G, et al. Bothnia [90]
dys t rophy caused by muta t ions in the ce l lu la r
retinaldehyde-binding protein gene (RLBP1) on
chromosome 15q26. Invest Ophthalmol Vis Sci, 1999,
40(5): 995-1000
王海青，等：RPE细胞的正常功能及其在眼科疾病中的作用第9期 885
Yamamoto H, Simon A, Eriksson U, et al. Mutations in [91]
the gene encoding 11-cis retinol dehydrogenase cause
delayed dark adaptation and fundus albipunctatus. Nat
Genet, 1999, 22(2): 188-91
Li R, Maminishkis A, Wang FE, et al. PDGF-C and -D [92]
induced proliferation/migration of human RPE is
abolished by inflammatory cytokines. Invest Ophthalmol
Vis Sci, 2007, 48(12): 5722-32
Leiderman YI, Miller JW. Proliferative vitreoretinopathy: [93]
pathobiology and therapeutic targets. Semin Ophthalmol,
2009, 24(2): 62-9
Saika S, Yamanaka O, Flanders KC, et al. Epithelial [94]
mesenchymal transition as a therapeutic target for
prevention of ocular tissue fibrosis. Endoc Met Immune
Disord Drug Targets, 2008, 8(1): 69-76
Liu Y, Ye F, Li Q, et al. Zeb1 represses [95] Mitf and regulates
pigment synthesis, cell proliferation, and epithelial
morphology. Invest Ophthalmol Vis Sci, 2009, 50(11):
5080-8
Tsukiji N, Nishihara D, Yajima I, et al. Mitf functions as [96]
an in ovo regulator for cell differentiation and proliferation
during development of the chick RPE. Dev Biol, 2009,
326(2): 335-46
Schouwey K, Aydin IT, Radtke F, et al. RBP-Jκ-dependent [97]
Notch signaling enhances retinal pigment epithelial cell
proliferation in transgenic mice. Oncogene, 2011, 30(3):
313-22
Ma XY, Pan L, Jin X, et al. Microphthalmia-associated [98]
transcription factor acts through PEDF to regulate RPE
cell migration. Exp Cell Res, 2012, 318(3): 251-61
Wildsoet CF, Oswald PJ, Clark S. Albinism: its implications [99]
for refractive development. Invest Ophthalmol Vis Sci,
2000, 41(1): 1-7
Shi Y, Li Y, Zhang D, et al. Exome sequencing identifies [100]
ZNF644 mutations in high myopia. PLoS Genet, 2011,
7(6): e1002084
Shi Y, Qu J, Zhang D, et al. Genetic variants at 13q12.12 [101]
are associated with high myopia in the Han Chinese
Population. Am J Hum Genet, 2011, 88(6): 805-13