Skip to main content

RPE barrier breakdown in diabetic retinopathy: seeing is believing

Journal of Ocular Biology, Diseases, and Informatics volume 4, pages 83–92 (2011)Cite this article

Abstract

Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in working-age Americans. DR is traditionally regarded as a disorder of blood–retina barriers, and the leakage of blood content is a major pathological characteristic of the disease. While the breakdown of the endothelial barrier in DR has been investigated extensively, the vascular leakage through the retinal pigment epithelium (RPE) barrier in the disease has not been widely acknowledged. As the blood content leaked through the RPE barrier causes excessive water influx to the retina, the breakdown of the RPE barrier is likely to play a causative role in the development of some forms of diabetic macular edema, a major cause of vision loss in DR. In this article, we will discuss the clinical evidences of the diabetes-induced RPE barrier breakdown, the alteration of the RPE in diabetes, the molecular and cellular mechanism of RPE barrier breakdown, and the research tools for the analysis of RPE barrier leakage. Finally, we will discuss the methodology and potential applications of our recently developed fluorescent microscopic imaging for the diabetes- or ischemia-induced RPE barrier breakdown in rodents.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Bill A. Blood circulation and fluid dynamics in the eye. Physiol Rev. 1975;55:383–417.

    PubMed  CAS  Google Scholar 

  2. Young RW, Bok D. Participation of the retinal pigment epithelium in the rod outer segment renewal process. J Cell Biol. 1969;42:392–403.

    PubMed  Article  CAS  Google Scholar 

  3. Benolken RM, Anderson RE, Wheeler TG. Membrane fatty acids associated with the electrical response in visual excitation. Science. 1973;182:1253–4.

    PubMed  Article  CAS  Google Scholar 

  4. Gordon WC, Rodriguez de Turco EB, Bazan NG. Retinal pigment epithelial cells play a central role in the conservation of docosahexaenoic acid by photoreceptor cells after shedding and phagocytosis. Curr Eye Res. 1992;11:73–83.

    PubMed  Article  CAS  Google Scholar 

  5. Philp NJ, Ochrietor JD, Rudoy C, Muramatsu T, Linser PJ. Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse. Invest Ophthalmol Vis Sci. 2003;44:1305–11.

    PubMed  Article  Google Scholar 

  6. Kumagai AK, Glasgow BJ, Pardridge WM. GLUT1 glucose transporter expression in the diabetic and nondiabetic human eye. Invest Ophthalmol Vis Sci. 1994;35:2887–94.

    PubMed  CAS  Google Scholar 

  7. Saari JC. Biochemistry of visual pigment regeneration: the Friedenwald lecture. Invest Ophthalmol Vis Sci. 2000;41:337–48.

    PubMed  CAS  Google Scholar 

  8. Bialek S, Miller SS. K+ and Cl− transport mechanisms in bovine pigment epithelium that could modulate subretinal space volume and composition. J Physiol. 1994;475:401–17.

    PubMed  CAS  Google Scholar 

  9. Hamann S. Molecular mechanisms of water transport in the eye. Int Rev Cytol. 2002;215:395–431.

    PubMed  Article  CAS  Google Scholar 

  10. Simo R, Villarroel M, Corraliza L, Hernandez C, Garcia-Ramirez M. The retinal 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.

    PubMed  Article  Google Scholar 

  11. Rizzolo LJ, Peng S, Luo Y, Xiao W. Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium. Prog Retin Eye Res. 2011;30:296–323.

    PubMed  Article  CAS  Google Scholar 

  12. Runkle EA, Antonetti DA. The blood-retinal barrier: structure and functional significance. Meth Mol Biol. 2011;686:133–48.

    Article  CAS  Google Scholar 

  13. Konari K, Sawada N, Zhong Y, Isomura H, Nakagawa T, Mori M. Development of the blood-retinal barrier in vitro: formation of tight junctions as revealed by occludin and ZO-1 correlates with the barrier function of chick retinal pigment epithelial cells. Exp Eye Res. 1995;61:99–108.

    PubMed  Article  CAS  Google Scholar 

  14. Rizzolo LJ. Polarity and the development of the outer blood-retinal barrier. Histol Histopathol. 1997;12:1057–67.

    PubMed  CAS  Google Scholar 

  15. Kojima S, Rahner C, Peng S, Rizzolo LJ. Claudin 5 is transiently expressed during the development of the retinal pigment epithelium. J Membr Biol. 2002;186:81–8.

    PubMed  Article  CAS  Google Scholar 

  16. Luo Y, Fukuhara M, Weitzman M, Rizzolo LJ. Expression of JAM-A, AF-6, PAR-3 and PAR-6 during the assembly and remodeling of RPE tight junctions. Brain Res. 2006;1110:55–63.

    PubMed  Article  CAS  Google Scholar 

  17. Daniele LL, Adams RH, Durante DE, Pugh Jr EN, Philp NJ. Novel distribution of junctional adhesion molecule-C in the neural retina and retinal pigment epithelium. J Comp Neurol. 2007;505:166–76.

    PubMed  Article  CAS  Google Scholar 

  18. Economopoulou M, Hammer J, Wang F, Fariss R, Maminishkis A, Miller SS. Expression, localization, and function of junctional adhesion molecule-C (JAM-C) in human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2009;50:1454–63.

    PubMed  Article  Google Scholar 

  19. Koh SW. The chick retinal pigment epithelium grown on permeable support demonstrates functional polarity. Exp Cell Res. 1989;181:331–47.

    PubMed  Article  CAS  Google Scholar 

  20. Shukla SY, Singh YK, Shukla D. Role of nectin-1, HVEM, and PILR-alpha in HSV-2 entry into human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2009;50:2878–87.

    PubMed  Article  Google Scholar 

  21. Tiwari V, Oh MJ, Kovacs M, Shukla SY, Valyi-Nagy T, Shukla D. Role for nectin-1 in herpes simplex virus 1 entry and spread in human retinal pigment epithelial cells. FEBS J. 2008;275:5272–85.

    PubMed  Article  CAS  Google Scholar 

  22. Marrs JA, Andersson-Fisone C, Jeong MC, Cohen-Gould L, Zurzolo C, Nabi IR, Rodriguez-Boulan E, Nelson WJ. Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules. J Cell Biol. 1995;129:507–19.

    PubMed  Article  CAS  Google Scholar 

  23. Vinores SA, Gadegbeku C, Campochiaro PA, Green WR. Immunohistochemical localization of blood-retinal barrier breakdown in human diabetics. Am J Pathol. 1989;134:231–5.

    PubMed  CAS  Google Scholar 

  24. Weinberger D, Fink-Cohen S, Gaton DD, Priel E, Yassur Y. Non-retinovascular leakage in diabetic maculopathy. Br J Ophthalmol. 1995;79:728–31.

    PubMed  Article  CAS  Google Scholar 

  25. Soliman W, Sander B, Jorgensen TM. Enhanced optical coherence patterns of diabetic macular oedema and their correlation with the pathophysiology. Acta Ophthalmol Scand. 2007;85:613–7.

    PubMed  Article  Google Scholar 

  26. Gaucher D, Sebah C, Erginay A, Haouchine B, Tadayoni R, Gaudric A, Massin P. Optical coherence tomography features during the evolution of serous retinal detachment in patients with diabetic macular edema. Am J Ophthalmol. 2008;145:289–96.

    PubMed  Article  Google Scholar 

  27. Voo I, Mavrofrides EC, Puliafito CA. Clinical applications of optical coherence tomography for the diagnosis and management of macular diseases. Ophthalmol Clin North Am. 2004;17:21–31.

    PubMed  Article  Google Scholar 

  28. Ozdemir H, Karacorlu M, Karacorlu S. Serous macular detachment in diabetic cystoid macular oedema. Acta Ophthalmol Scand. 2005;83:63–6.

    PubMed  Article  Google Scholar 

  29. Marmor MF. Mechanisms of fluid accumulation in retinal edema. Doc Ophthalmol. 1999;97:239–49.

    PubMed  Article  CAS  Google Scholar 

  30. Vinores SA, Derevjanik NL, Ozaki H, Okamoto N, Campochiaro PA. Cellular mechanisms of blood-retinal barrier dysfunction in macular edema. Doc Ophthalmol. 1999;97:217–28.

    PubMed  Article  CAS  Google Scholar 

  31. Wang J, Xu X, Elliott MH, Zhu M, Le Y. Müller cell-derived VEGF is essential for diabetes-induced retinal inflammation and vascular leakage. Diabetes. 2010;59:2297–3005.

    PubMed  Article  CAS  Google Scholar 

  32. Xu HZ, Le YZ. Significance of outer blood-retina barrier breakdown in diabetes and ischemia. Invest Ophthalmol Vis Sci. 2011;52:2160–4.

    PubMed  Article  CAS  Google Scholar 

  33. Aizu Y, Oyanagi K, Hu J, Nakagawa H. Degeneration of retinal neuronal processes and pigment epithelium in the early stage of the streptozotocin-diabetic rats. Neuropathology. 2002;22:161–70.

    PubMed  Article  Google Scholar 

  34. Vinores SA, Van Niel E, Swerdloff JL, Campochiaro PA. Electron microscopic immunocytochemical demonstration of blood-retinal barrier breakdown in human diabetics and its association with aldose reductase in retinal vascular endothelium and retinal pigment epithelium. Histochem J. 1993;25:648–63.

    PubMed  Article  CAS  Google Scholar 

  35. Vinores SA, Van Niel E, Swerdloff JL, Campochiaro PA. Electron microscopic immunocytochemical evidence for the mechanism of blood-retinal barrier breakdown in galactosemic rats and its association with aldose reductase expression and inhibition. Exp Eye Res. 1993;57:723–35.

    PubMed  Article  CAS  Google Scholar 

  36. Kirber WM, Nichols CW, Grimes PA, Winegrad AI, Laties AM. A permeability defect of the retinal pigment epithelium. Occurrence in early streptozocin diabetes. Arch Ophthalmol. 1980;98:725–8.

    PubMed  Article  CAS  Google Scholar 

  37. Pautler EL, Ennis SR. The effect of induced diabetes on the electroretinogram components of the pigmented rat. Invest Ophthalmol Vis Sci. 1980;19:702–5.

    PubMed  CAS  Google Scholar 

  38. MacGregor LC, Matschinsky FM. Experimental diabetes mellitus impairs the function of the retinal pigmented epithelium. Metabolism. 1986;35:28–34.

    PubMed  Article  CAS  Google Scholar 

  39. Rimmer T, Linsenmeier RA. Resistance of diabetic rat electroretinogram to hypoxemia. Invest Ophthalmol Vis Sci. 1993;34:3246–52.

    PubMed  CAS  Google Scholar 

  40. Decanini A, Karunadharma PR, Nordgaard CL, Feng X, Olsen TW, Ferrington DA. Human retinal pigment epithelium proteome changes in early diabetes. Diabetologia. 2008;51:1051–61.

    PubMed  Article  CAS  Google Scholar 

  41. Bai Y, Ma JX, Guo J, Wang J, Zhu M, Chen Y, Le YZ. Muller cell-derived VEGF is a significant contributor to retinal neovascularization. J Pathol. 2009;219:446–54.

    PubMed  Article  CAS  Google Scholar 

  42. Aiello LP, Wong JS. Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int Suppl. 2000;77:S113–9.

    PubMed  Article  CAS  Google Scholar 

  43. Murata T, Nakagawa K, Khalil A, Ishibashi T, Inomata H, Sueishi K. The relation between expression of vascular endothelial growth factor and breakdown of the blood-retinal barrier in diabetic rat retinas. Lab Invest. 1996;74:819–25.

    PubMed  CAS  Google Scholar 

  44. Hammes HP, Lin J, Bretzel RG, Brownlee M, Breier G. Upregulation of the vascular endothelial growth factor/vascular endothelial growth factor receptor system in experimental background diabetic retinopathy of the rat. Diabetes. 1998;47:401–6.

    PubMed  Article  CAS  Google Scholar 

  45. Mousa SA, Lorelli W, Campochiaro PA. Role of hypoxia and extracellular matrix-integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells. J Cell Biochem. 1999;74:135–43.

    PubMed  Article  CAS  Google Scholar 

  46. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2003;110:1690–6.

    PubMed  Article  Google Scholar 

  47. Qaum T, Xu Q, Joussen AM, Clemens MW, Qin W, Miyamoto K, Hassessian H, Wiegand SJ, Rudge J, Yancopoulos GD, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 2001;42:2408–13.

    PubMed  CAS  Google Scholar 

  48. Korte GE, Cushin S, Delman N. Permeability of regenerating and atrophic choriocapillaris in the rabbit. Acta Anat (Basel). 1989;134:144–50.

    Article  CAS  Google Scholar 

  49. Ghassemifar R, Lai CM, Rakoczy PE. VEGF differentially regulates transcription and translation of ZO-1alpha+ and ZO-1alpha- and mediates trans-epithelial resistance in cultured endothelial and epithelial cells. Cell Tissue Res. 2006;323:117–25.

    PubMed  Article  CAS  Google Scholar 

  50. Kannan R, Zhang N, Sreekumar PG, Spee CK, Rodriguez A, Barron E, Hinton DR. Stimulation of apical and basolateral VEGF-A and VEGF-C secretion by oxidative stress in polarized retinal pigment epithelial cells. Mol Vis. 2006;12:1649–59.

    PubMed  CAS  Google Scholar 

  51. Hartnett ME, Lappas A, Darland D, McColm JR, Lovejoy S, D'Amore PA. Retinal pigment epithelium and endothelial cell interaction causes retinal pigment epithelial barrier dysfunction via a soluble VEGF-dependent mechanism. Exp Eye Res. 2003;77:593–9.

    PubMed  Article  CAS  Google Scholar 

  52. Ablonczy Z, Crosson CE. VEGF modulation of retinal pigment epithelium resistance. Exp Eye Res. 2007;85:762–71.

    PubMed  Article  CAS  Google Scholar 

  53. Miyamoto N, de Kozak Y, Jeanny JC, Glotin A, Mascarelli F, Massin P, BenEzra D, Behar-Cohen F. Placental growth factor-1 and epithelial haemato-retinal barrier breakdown: potential implication in the pathogenesis of diabetic retinopathy. Diabetologia. 2007;50:461–70.

    PubMed  Article  CAS  Google Scholar 

  54. Cai J, Wu L, Qi X, Shaw L, Li Calzi S, Caballero S, Jiang WG, Vinores SA, Antonetti D, Ahmed A, et al. Placenta growth factor-1 exerts time-dependent stabilization of adherens junctions following VEGF-induced vascular permeability. PLoS One. 2011;6:e18076.

    PubMed  Article  CAS  Google Scholar 

  55. Ablonczy Z, Prakasam A, Fant J, Fauq A, Crosson C, Sambamurti K. Pigment epithelium-derived factor maintains retinal pigment epithelium function by inhibiting vascular endothelial growth factor-R2 signaling through gamma-secretase. J Biol Chem. 2009;284:30177–86.

    PubMed  Article  CAS  Google Scholar 

  56. Peng S, Adelman RA, Rizzolo LJ. Minimal effects of VEGF and anti-VEGF drugs on the permeability or selectivity of RPE tight junctions. Invest Ophthalmol Vis Sci. 2010;51:3216–25.

    PubMed  Article  Google Scholar 

  57. Villarroel M, Garcia-Ramirez M, Corraliza L, Hernandez C, Simo R. Effects 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;89:913–20.

    PubMed  Article  CAS  Google Scholar 

  58. Ablonczy Z, Dahrouj M, Tang PH, Liu Y, Sambamurti K, Marmorstein AD, Crosson CE. Human retinal pigment epithelium cells as functional models for the RPE in vivo. Invest Ophthalmol Vis Sci. 2011;52(12):8614–20.

    PubMed  Article  CAS  Google Scholar 

  59. Villarroel M, Garcia-Ramirez M, Corraliza L, Hernandez C, Simo R. High glucose concentration leads to differential expression of tight junction proteins in human retinal pigment epithelial cells. Endocrinol Nutr. 2009;56:53–8.

    PubMed  Article  CAS  Google Scholar 

  60. Bailey TA, Kanuga N, Romero IA, Greenwood J, Luthert PJ, Cheetham ME. Oxidative stress affects the junctional integrity of retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2004;45:675–84.

    PubMed  Article  Google Scholar 

  61. Chang C, Wang X, Caldwell RB. Serum opens tight junctions and reduces ZO-1 protein in retinal epithelial cells. J Neurochem. 1997;69:859–67.

    PubMed  Article  CAS  Google Scholar 

  62. Chang CW, Ye L, Defoe DM, Caldwell RB. Serum inhibits tight junction formation in cultured pigment epithelial cells. Invest Ophthalmol Vis Sci. 1997;38:1082–93.

    PubMed  CAS  Google Scholar 

  63. Garcia-Ramirez M, Hernandez C, Ruiz-Meana M, Villarroel M, Corraliza L, Garcia-Dorado D, Simo R. Erythropoietin protects retinal pigment epithelial cells against the increase of permeability induced by diabetic conditions: essential role of JAK2/PI3K signaling. Cell Signal. 2011;23:1596–602.

    PubMed  Article  CAS  Google Scholar 

  64. Chen Y, Yang P, Li F, Kijlstra A. The effects of Th17 cytokines on the inflammatory mediator production and barrier function of ARPE-19 cells. PLoS One. 2011;6:e18139.

    PubMed  Article  CAS  Google Scholar 

  65. Abe T, Sugano E, Saigo Y, Tamai M. Interleukin-1beta and barrier function of retinal pigment epithelial cells (ARPE-19): aberrant expression of junctional complex molecules. Invest Ophthalmol Vis Sci. 2003;44:4097–104.

    PubMed  Article  Google Scholar 

  66. Zhou J, He S, Zhang N, Spee C, Zhou P, Ryan SJ, Kannan R, Hinton DR. Neutrophils compromise retinal pigment epithelial barrier integrity. J Biomed Biotechnol. 2010;2010:289360.

    PubMed  Google Scholar 

  67. Hiukka A, Leinonen E, Jauhiainen M, Sundvall J, Ehnholm C, Keech AC, Taskinen MR. Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus. Diabetologia. 2007;50:2067–75.

    PubMed  Article  CAS  Google Scholar 

  68. Trudeau K, Roy S, Guo W, Hernandez C, Villarroel M, Simo R, Roy S. Fenofibric acid reduces fibronectin and collagen type IV overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability. Invest Ophthalmol Vis Sci. 2011;52:6348–54.

    PubMed  Article  CAS  Google Scholar 

  69. Villarroel M, Garcia-Ramirez M, Corraliza L, Hernandez C, Simo R. Fenofibric acid prevents retinal pigment epithelium disruption induced by interleukin-1beta by suppressing AMP-activated protein kinase (AMPK) activation. Diabetologia. 2011;54:1543–53.

    PubMed  Article  CAS  Google Scholar 

  70. Miranda S, Gonzalez-Rodriguez A, Garcia-Ramirez M, Revuelta-Cervantes J, Hernandez C, Simo R, Valverde AM. Beneficial effects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions. J Cell Physiol. 2011. doi:10.1002/jcp.22970.

  71. Tso MO, Cunha-Vaz JG, Shih CY, Jones CW. Clinicopathologic study of blood-retinal barrier in experimental diabetes mellitus. Arch Ophthalmol. 1980;98:2032–40.

    PubMed  Article  CAS  Google Scholar 

  72. Gregor Z, Ryan SJ. Blood-retinal barrier after blunt trauma to the eye. Graefe’s Arch Clinical Exp Ophthalmol. 1982;219:205–8.

    Article  CAS  Google Scholar 

  73. Korte GE, Bellhorn RW, Burns MS. Ultrastructure of blood-retinal barrier permeability in rat phototoxic retinopathy. Invest Ophthalmol Vis Sci. 1983;24:962–71.

    PubMed  CAS  Google Scholar 

  74. Uyama M, Matsunaga H, Matsubara T, Fukushima I, Takahashi K, Nishimura T. Indocyanine green angiography and pathophysiology of multifocal posterior pigment epitheliopathy. Retina. 1999;19:12–21.

    PubMed  Article  CAS  Google Scholar 

  75. Yoshioka H, Katsume Y, Ishibashi R. Experimental central serous chorioretinopathy. II: further clinical findings. Kurume Med J. 1981;28:189–96.

    PubMed  Article  CAS  Google Scholar 

  76. Soliman W, Sander B, Hasler PW, Larsen M. Correlation between intraretinal changes in diabetic macular oedema seen in fluorescein angiography and optical coherence tomography. Acta Ophthalmol. 2008;86:34–9.

    PubMed  Article  Google Scholar 

  77. Smith LE, Wesolowski E, McLellan A, Kostyk SK, D'Amato R, Sullivan R, D'Amore PA. Oxygen-induced retinopathy in the mouse. Invest Ophthalmol Vis Sci. 1994;35:101–11.

    PubMed  CAS  Google Scholar 

  78. Do carmo A, Ramos P, Reis A, Proenca R, Cunha-vaz JG. Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes. Exp Eye Res. 1998;67:569–75.

    PubMed  Article  CAS  Google Scholar 

  79. Googe JM, Hirose T, Apple DJ, Melgen S. Vitreous hemorrhage secondary to age-related macular degeneration. Surv Ophthalmol. 1987;32:123–30.

    PubMed  Article  CAS  Google Scholar 

  80. el Baba F, Jarrett 2nd WH, Harbin Jr TS, Fine SL, Michels RG, Schachat AP, Green WR. Massive hemorrhage complicating age-related macular degeneration. Clinicopathologic correlation and role of anticoagulants. Ophthalmology. 1986;93:1581–92.

    PubMed  Google Scholar 

  81. Takeuchi A, Kricorian G, Marmor MF. Albumin movement out of the subretinal space after experimental retinal detachment. Invest Ophthalmol Vis Sci. 1995;36:1298–305.

    PubMed  CAS  Google Scholar 

  82. Aizu Y, Katayama H, Takahama S, Hu J, Nakagawa H, Oyanagi K. Topical instillation of ciliary neurotrophic factor inhibits retinal degeneration in streptozotocin-induced diabetic rats. Neuroreport. 2003;14:2067–71.

    PubMed  Article  CAS  Google Scholar 

  83. Negi A, Marmor MF. Experimental serous retinal detachment and focal pigment epithelial damage. Arch Ophthalmol. 1984;102:445–9.

    PubMed  Article  CAS  Google Scholar 

  84. Nicholson BP, Schachat AP. A review of clinical trials of anti-VEGF agents for diabetic retinopathy. Graefe’s Arch Clin Exp Ophthalmol. 2011;248:915–30.

    Article  Google Scholar 

  85. Le YZ. Conditional gene targeting: dissecting the cellular mechanisms of retinal degenerations. J Ophthalmol. 2011;2011:806783.

    PubMed  Google Scholar 

  86. Le YZ, Zheng W, Rao PC, Zheng L, Anderson RE, Esumi N, Zack DJ, Zhu M. Inducible expression of cre recombinase in the retinal pigmented epithelium. Invest Ophthalmol Vis Sci. 2008;49:1248–53.

    PubMed  Article  Google Scholar 

  87. Le YZ, Bai Y, Zhu M, Zheng L. Temporal requirement of RPE-derived VEGF in the development of choroidal vasculature. J Neurochem. 2010;112:1584–92.

    PubMed  Article  CAS  Google Scholar 

  88. Iacovelli J, Zhao C, Wolkow N, Veldman P, Gollomp K, Ojha P, Lukinova N, King A, Feiner L, Esumi N, et al. Generation of Cre transgenic mice with postnatal RPE-specific ocular expression. Invest Ophthalmol Vis Sci. 2011;52:1378–83.

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Gennadiy Moiseyev for the critical reading of this manuscript. Our research is supported by NIH grants R01EY20900, P20RR17703, P20RR024215, and P30EY21725, American Diabetes Association grant 1-10-BS-94, Beckman Initiative for Macular Research Grant 1003, and Oklahoma Center for the Advancement of Science and Technology contract HR09-058.

Author information

Affiliations

  1. Department of Medicine Endocrinology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Hui-Zhuo Xu, Zhiming Song, Shuhua Fu, Meili Zhu & Yun-Zheng Le

  2. Department of Cell Biology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Yun-Zheng Le

  3. Harold Hamm Diabetes Center, The University of Oklahoma Health Sciences Center, 941 S. L. Young Blvd., BSEB 302G, Oklahoma City, OK, 73104, USA

    Hui-Zhuo Xu, Zhiming Song, Shuhua Fu, Meili Zhu & Yun-Zheng Le

  4. Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, 410008, China

    Hui-Zhuo Xu

Authors
  1. Hui-Zhuo Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhiming Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shuhua Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meili Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yun-Zheng Le
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yun-Zheng Le.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Xu, HZ., Song, Z., Fu, S. et al. RPE barrier breakdown in diabetic retinopathy: seeing is believing. j ocul biol dis inform 4, 83–92 (2011). https://doi.org/10.1007/s12177-011-9068-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12177-011-9068-4

Keywords

  • Diabetic retinopathy
  • Macular edema
  • RPE
  • Barrier
  • Leakage
  • Fluorescent microscopy