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Diabetic Retinopathy pp 29–72Cite as

The Diabetic Retina: Anatomy and Pathophysiology

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Abstract

Throughout the world diabetic retinopathy (DR) has emerged as a major cause of permanent loss of vision among people over the age of 20 years. Retinopathy has generally been considered a vasculopathy that results from breakdown of the blood-retinal barrier and closure of retinal capillaries. Recent evidence, however, suggests that DR begins as a neuro-retinopathy with vascular changes occurring later during the disease.

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References

  1. Abiko T, Abiko A, Clermont AC, et al. Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. Diabetes. 2003;52(3):829–37.

    Article  CAS  PubMed  Google Scholar 

  2. Adamiec-Mroczek J, Oficjalska-Młyńczak J. Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes – role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2008;246:1665–70.

    Article  CAS  PubMed  Google Scholar 

  3. Adamis AP, Berman AJ. Immunological mechanisms in the pathogenesis of diabetic retinopathy. Semin Immunopathol. 2008;30(2):65–84.

    Article  CAS  PubMed  Google Scholar 

  4. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am J Ophthalmol. 1994;118:445–50.

    Article  CAS  PubMed  Google Scholar 

  5. Adler AJ, Severin KM. Proteins of the bovine interphotoreceptor matrix – tissues of origin. Exp Eye Res. 1981;2:755–69.

    Article  Google Scholar 

  6. Aguilera G, Kiss A. Regulation of the hypothalamic-pituitary-adrenal axis and vasopressin secretion. Role of angiotensin II. Adv Exp Med Biol. 1996;396:105–12.

    Article  CAS  PubMed  Google Scholar 

  7. Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes. 1997;46:1473–80.

    Article  CAS  PubMed  Google Scholar 

  8. Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol. 1999;14:223–32.

    Article  CAS  PubMed  Google Scholar 

  9. Antonetti DA, Barber AJ, Bronson SK, Freeman WM, Gardner TW, Jefferson LS, Kester M, Kimball SR, Krady JK, LaNoue KF, et al. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes. 2006;55:2401–11.

    Article  CAS  PubMed  Google Scholar 

  10. Antonetti DA, Barber AJ, Khin S, et al. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group. Diabetes. 1998;47:1953–9.

    Article  CAS  PubMed  Google Scholar 

  11. Archer D, Krill AE, Newell FW. Fluorescein studies of normal choroidal circulation. Am J Ophthalmol. 1970;69:543–54.

    Article  CAS  PubMed  Google Scholar 

  12. Arend O, Remky A, Harris A, et al. Macular microcirculation in cystoid maculopathy of diabetic patients [see comments]. Br J Ophthalmol. 1995;79:628–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bainbridge JW, Mistry A, De Alwis M, et al. Inhibition of retinal neovascularization by gene transfer of soluble VEGF receptor sFlt-1. Gene Ther. 2002;9:320–6.

    Article  CAS  PubMed  Google Scholar 

  14. Ballantyne AJ, Loewenstein A. The pathology of diabetic retinopathy. Trans Ophthalmol Soc. 1943;63:95–113.

    Google Scholar 

  15. Barber AJ, Antonetti DA, Kern TS, Reiter CE, Soans RS, Krady JK, Levison SW, Gardner TW, Bronson SK. The Ins2Akita mouse as a model of early retinal complications in diabetes. Invest Ophthalmol Vis Sci. 2005;46:2210–8.

    Article  PubMed  Google Scholar 

  16. Bates DO. The chronic effect of vascular endothelial growth factor on individually perfused frog mesenteric microvessels. J Physiol. 1998;513:225–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bates DO, Curry FE. Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am J Physiol. 1996;271:H2520–8.

    CAS  PubMed  Google Scholar 

  18. Bates DO, Hillman NJ, Williams B, et al. Regulation of microvascular permeability by vascular endothelial growth factors. J Anat. 2002;200:581–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bek T, Lund-Andersen H. Localised blood-retinal barrier leakage and retinal light sensitivity in diabetic retinopathy. Br J Ophthalmol. 1990;74:388–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Beltramo E, Pomero F, Allione A, D’Alu F, Ponte E, Porta M. Pericyte adhesion is impaired on extracellular matrix produced by endothelial cells in high hexose concentrations. Diabetologia. 2002;45:416–9.

    Article  CAS  PubMed  Google Scholar 

  21. Benjamin LE. Glucose, VEGF-A, and diabetic complications. Am J Pathol. 2001;158:1181–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bolton SJ, Anthony DC, Perry VH. Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood-brain barrier breakdown in vivo. Neuroscience. 1998;86:1245–57.

    Article  CAS  PubMed  Google Scholar 

  23. Bolton WK, Cattran DC, Williams ME, et al. Randomized trial of an inhibitor of advanced glycation end products in diabetic nephropathy. Am J Nephrol. 2004;24:32–40.

    Article  CAS  PubMed  Google Scholar 

  24. Brooks Jr HL, Caballero Jr S, Newell CK, et al. Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Ophthalmol. 2004;122:1801–7.

    Article  CAS  PubMed  Google Scholar 

  25. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813–20.

    Article  CAS  PubMed  Google Scholar 

  26. Brucklacher RM, Patel KM, Vanguilder HD, Bixler GV, Barber AJ, Antonetti DA, Lin CM, Lanoue KF, Gardner TW, Bronson SK, Freeman WM. Whole genome assessment of the retinal response to diabetes reveals a progressive neurovascular inflammatory response. BMC Med Genomics. 2006;1:26.

    Article  CAS  Google Scholar 

  27. Budzynski E, Wangsa-Wirawan N, Padnick-Silver L, Hatchell D, Linsenmeier R. Intraretinal pH in diabetic cats. Curr Eye Res. 2005;30:229–40.

    Article  CAS  PubMed  Google Scholar 

  28. Bursell SE, Clermont AC, Kinsley BT, Simonson DC, Aiello LM, Wolpert HA. Retinal blood flow changes in patients with insulin-dependent diabetes mellitus and no diabetic retinopathy. Invest Ophthalmol Vis Sci. 1996;37:886–97.

    CAS  PubMed  Google Scholar 

  29. Chakravarthy U, Gardiner TA, Anderson P, et al. The effect of endothelin I on the retinal microvascular pericyte. Microvasc Res. 1992;43:241–54.

    Article  CAS  PubMed  Google Scholar 

  30. Charonis AS, Reger LA, Dege JE, et al. Laminin alterations after in vitro nonenzymatic glycosylation. Diabetes. 1990;39:807–14.

    Article  CAS  PubMed  Google Scholar 

  31. Chaturvedi N, Sjolie AK, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in insulin-Dependent Diabetes Mellitus. Lancet. 1998;351:28–31.

    Article  CAS  PubMed  Google Scholar 

  32. Chen P, Guo AM, Edwards PA, et al. Role of NADPH oxidase and ANG II in diabetes-induced retinal leukostasis. Am J Physiol Regul Integr Comp Physiol. 2007;293:R1619–29.

    Article  CAS  PubMed  Google Scholar 

  33. Ciulla TA, Harris A, Latkany P, Piper HC, Arend O, Garzozi H, Martin B. Ocular perfusion abnormalities in diabetes. Acta Ophthalmol Scand. 2002;80:468–77.

    Article  PubMed  Google Scholar 

  34. Clarke H, Marano CW, Peralta Soler A, Mullin JM. Modification of tight junction function by protein kinase C isoforms. Adv Drug Deliv Rev. 2000;41:283–301.

    Article  CAS  PubMed  Google Scholar 

  35. Cogan DG, Toussaint D, Kuwabara T. Retinal vascular patterns. Part IV. Diabetic retinopathy. Arch Ophthalmol. 1961;66:366–78.

    Article  CAS  PubMed  Google Scholar 

  36. Cox O, Stitt AW, Simpson DA, Gardiner TA. Sources of PDGF expression in murine retina and the effect of short-term diabetes. Mol Vis. 2003;10:665–72.

    Google Scholar 

  37. Craven PA, Phillip SL, Melham MF, et al. Overexpression of Mn2+ superoxide dismutase increases in collagen accumulation induced by culture in mesangial cells in high-media glucose. Metabolism. 2001;50:1043–8.

    Article  CAS  PubMed  Google Scholar 

  38. Craven PA, Studer RK, Felder J, et al. Nitric oxide inhibition of transforming growth factor-beta and collagen synthesis in mesangial cells. Diabetes. 1997;46:671–81.

    Article  CAS  PubMed  Google Scholar 

  39. Cringle S, Yu DY, Alder V, Su EN. Oxygen tension and blood flow in the retina of normal and diabetic rats. Adv Exp Med Biol. 1992;317:787–91.

    Article  CAS  PubMed  Google Scholar 

  40. Culman J, Hohle S, Qadri F, et al. Angiotensin as neuromodulator/neurotransmitter in central control of body fluid and electrolyte homeostasis. Clin Exp Hypertens. 1995;17:281–93.

    Article  CAS  PubMed  Google Scholar 

  41. Cunha-Vaz J, Faria de Abreu JR, Campos AJ. Early breakdown of the blood-retinal barrier in diabetes. Br J Ophthalmol. 1975;59:649–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Curcio CA, Allen KA. Topography of ganglion cells in human retina. J Comp Neurol. 1990;300:5–25.

    Article  CAS  PubMed  Google Scholar 

  43. Curtis TM, Gardiner TA, Stitt AW. Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis? Eye (Lond). 2009;23:1496–508.

    Article  CAS  Google Scholar 

  44. Degenhardt TP, Thorpe SR, Baynes JW. Chemical modification of proteins by methylglyoxal. Cell Mol Biol. 1998;44:1139–45.

    CAS  PubMed  Google Scholar 

  45. de Gooyer TE, Stevenson KA, Humphries P, et al. Retinopathy is reduced during experimental diabetes in a mouse model of outer retinal degeneration. Invest Ophthalmol Vis Sci. 2006;47:5561–8.

    Article  PubMed  Google Scholar 

  46. Dodge AB, Hechtman HB, Shepro D. Microvascular endothelial-derived autacoids regulate pericyte contractility. Cell Motil Cytoskeleton. 1991;18:180–8.

    Article  CAS  PubMed  Google Scholar 

  47. Dowling JE, Boycott BB. Organization of the primate retina – electron microscopy. Proc R Soc Ser B. 1966;166:80–111.

    Article  CAS  Google Scholar 

  48. Droge W. Free radicals and the physiological control of cell function. Physiol Rev. 2002;83:47–95.

    Article  Google Scholar 

  49. Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest. 2001;108:1341–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Du XL, Edelstein D, Rossetti L, et al. Hyperglycemia-induced mitochondrial superoxide overproduction activates the hexosamine pathway and induces plasminogen activator inhibitor-1 expression by increasing Sp1 glycosylation. Proc Natl Acad Sci U S A. 2000;97:12222–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Engerman RL, Kern TX, Larson ME. Nerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs. Diabetologia. 1994;37:141–4.

    Article  CAS  PubMed  Google Scholar 

  52. Ernest JT. Macrocirculation and microcirculation of the retina. In: Ryan SJ, Ogden TE, editors. Retina, vol. 1. St. Louis: CV Mosby; 1989. p. 65–6.

    Google Scholar 

  53. Fanning AS, Ma TY, Anderson JM. Isolation and functional characterization of the actin binding region in the tight junction protein ZO-1. FASEB J. 2002;16:1835–7.

    CAS  PubMed  Google Scholar 

  54. Feeney-Burns L, Burns RP, Gao C-L. Age-related macular changes in humans over 90 years old. Am J Ophthalmol. 1990;109:265–78.

    Article  CAS  PubMed  Google Scholar 

  55. Felinski EA, Antonetti DA. Glucocorticoid regulation of endothelial cell tight junction gene expression: novel treatments for diabetic retinopathy. Curr Eye Res. 2005;30:949–57.

    Article  CAS  PubMed  Google Scholar 

  56. Ferrara N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 1999;56:794–814.

    Article  CAS  PubMed  Google Scholar 

  57. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25:581–611.

    Article  CAS  PubMed  Google Scholar 

  58. Ferrari-Dileo G, Davis EB, Anderson DR. Response of retinal vasculature to phenylephrine. Invest Ophthalmol Vis Sci. 1990;30:1181–2.

    Google Scholar 

  59. Fine BS, Brucker AJ. Macular edema and cystoid macular edema. Am J Ophthalmol. 1981;92:466–81.

    Article  CAS  PubMed  Google Scholar 

  60. Fong DS, Aiello L, Gardner TW, et al. American Diabetes Association. Retinopathy in diabetes. Diabetes Care. 2004;27(Suppl 4):S84–7.

    Google Scholar 

  61. Fruttiger M. Development of the mouse retinal vasculature: angiogenesis versus vasculogenesis. Invest Ophthalmol Vis Sci. 2002;43:522–7.

    PubMed  Google Scholar 

  62. Fukumura D, Gohongi T, Kadambi A, et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A. 2001;98:2604–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fukushima I, McLeod DS, Lutty GA. Intrachoroidal microvascular abnormality: a previously unrecognized form of choroidal neovascularization. Am J Ophthalmol. 1997;124:473–87.

    Article  CAS  PubMed  Google Scholar 

  64. Funatsu H, Yamashita H, Ikeda T, et al. Angiotensin II and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Br J Ophthalmol. 2002;86:311–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Funatsu H, Yamashita H, Ikeda T, et al. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2003;110:1690–6.

    Article  PubMed  Google Scholar 

  66. Gardiner TA, Archer DB, Curtis TM, Stitt AW. Arteriolar involvement in the microvascular lesions of diabetic retinopathy: implications for pathogenesis. Microcirculation. 2007;14:25–38.

    Article  PubMed  Google Scholar 

  67. Gardiner TA, Stitt AW, Anderson HR, Archer DB. Selective loss of vascular smooth muscle cells in the retinal microcirculation of diabetic dogs. Br J Ophthalmol. 1994;78:54–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gardner TW, Lieth E, Khin SA, et al. Astrocytes increase barrier properties and ZO-1 expression in retinal vascular endothelial cells. Invest Ophthalmol Vis Sci. 1997;38:2423–7.

    CAS  PubMed  Google Scholar 

  69. Gass JDM, Anderson DR, Davis EB. A clinical, fluorescein angiographic, and electron microscopic correlation of cystoid macular edema. Am J Ophthalmol. 1985;100:82–6.

    Article  CAS  PubMed  Google Scholar 

  70. Gaudry M, Bregerie O, Andrieu V, et al. Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood. 1997;90:4153–61.

    CAS  PubMed  Google Scholar 

  71. Gehlbach P, Demetriades AM, Yamamoto S, et al. Periocular gene transfer of sFlt-1 suppresses ocular neovascularization and vascular endothelial growth factor-induced breakdown of the blood-retinal barrier. Hum Gene Ther. 2003;14:129–41.

    Article  CAS  PubMed  Google Scholar 

  72. Gerhardinger C, Dagher Z, Sebastiani P, Park YS, Lorenzi M. The transforming growth factor-β pathway is a common target of drugs that prevent experimental diabetic retinopathy. Diabetes. 2009;58:1659–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Giardino I, Edelstein D, Brownlee M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation end-products in bovine endothelial cells. J Clin Invest. 1996;97:1422–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Giebel SJ, Menicucci G, McGuire PG, Das A. Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrier. Lab Invest. 2005;85:597–607.

    Article  CAS  PubMed  Google Scholar 

  75. Gilbert RD, Kelly DJ, Cox AJ, et al. Angiotensin converting enzyme inhibition reduces retinal overexpression of vascular endothelial growth factor and hyperpermeability in experimental diabetes. Diabetologia. 2000;43:1360–7.

    Article  CAS  PubMed  Google Scholar 

  76. Gillies MC, Su T, Stayl J, et al. Effect of high glucose on permeability of retinal capillary endothelium in vitro. Invest Ophthalmol Vis Sci. 1997;38:635–42.

    Google Scholar 

  77. Greene DA, Arezzo JC, Brown MB. Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group. Neurology. 1999;53:580–91.

    Article  CAS  PubMed  Google Scholar 

  78. Grunwald JE, Riva CE, Baine J, Brucker AJ. Total retinal volumetric blood flow rate in diabetic patients with poor glycemic control. Invest Ophthalmol Vis Sci. 1992;33:356–63.

    CAS  PubMed  Google Scholar 

  79. Guigliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996;19:257–67.

    Article  Google Scholar 

  80. Hammes HP, Lin J, Renner O, Shani M, Lundqvist A, Betsholtz C, Brownlee M, Deutsch U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes. 2002;51:3107–12.

    Article  CAS  PubMed  Google Scholar 

  81. Handelman GJ, Snodderly DM, Krinsky NI, et al. Biological control of primate macular pigment – biochemical and densitometric studies. Invest Ophthalmol Vis Sci. 1991;32:257–67.

    CAS  PubMed  Google Scholar 

  82. Hart GW. Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu Rev Biochem. 1997;66:315–35.

    Article  CAS  PubMed  Google Scholar 

  83. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.

    Article  CAS  PubMed  Google Scholar 

  84. Henkind P. New observations on the radial peripapillary capillaries. Invest Ophthalmol. 1967;6:103.

    CAS  PubMed  Google Scholar 

  85. Hewitt AT, Adler R. The retinal pigment epithelium and interphotoreceptor matrix – structure and specialized functions. In: Ryan SJ, Ogden TE, editors. Retina, vol. 1. St. Louis: CV Mosby; 1989. p. 57–64.

    Google Scholar 

  86. Hoffmann J, Feng Y, von Hagen F, Hillenbrand A, Lin J, Erber R, Vajkoczy P, Gourzoulidou E, Waldmann H, Giannis A, et al. Endothelial survival factors and spatial completion, but not pericyte coverage of retinal capillaries determine vessel plasticity. FASEB J. 2005;19:2035–6.

    Google Scholar 

  87. Hogan MJ, Alvarado JA, Weddell JE. The retina. In:Histology of the human eye. Philadelphia: WB Saunders; 1971. p. 393–522.

    Google Scholar 

  88. Hogan MJ, Feeney L. Ultrastructure of the retinal vessels. Part 1. The larger vessels. J Ultrastruct Res. 1963;9:10–28.

    Article  Google Scholar 

  89. Horie K, Miyata T, Maeda K, et al. Immunohistochemical colocalization of glycoxidation products and lipid peroxidation products in diabetic renal glomerular lesions. Implication for glycoxidative stress in the pathogenesis of diabetic nephropathy. J Clin Invest. 1997;100:2995–3004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hseuh WA, Law RE. Cardiovascular risk continuum: implications of insulin resistance and diabetes. Am J Med. 1998;105:4S–14S.

    Article  Google Scholar 

  91. Huijberts MSP, Wolffenbuttel BH, Boudier HA, et al. Aminoguanidine treatment increases elasticity and decreases fluid filtration of large arteries from diabetic rats. J Clin Invest. 1993;92:1407–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer. 2007;121:2372–80.

    Google Scholar 

  93. Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science. 1996;272:728–31.

    Article  CAS  PubMed  Google Scholar 

  94. Ito M, Oliverio MI, Mannon PJ, et al. Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci U S A. 1995;92:3521–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science. 2001;292:468–72.

    Article  CAS  PubMed  Google Scholar 

  96. Jerdan JA, Kao L, Glaser BM. The inner limiting membrane: a modified basement membrane? Invest Ophthalmol Vis Sci. 1986;27(suppl):230a.

    Google Scholar 

  97. Jones CW, Cunha-Vaz J, Zweig KO, Stein M. Kinetic vitreous fluorophotometry in experimental diabetes. Arch Ophthalmol. 1979;97:1941–3.

    Article  CAS  PubMed  Google Scholar 

  98. Joussen AM, Poulaki V, Le ML, Koizumi K, Esser C, Janicki H, Schraermeyer U, Kociok N, Fauser S, Kirchhof B, et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 2004;18:1450–2.

    CAS  PubMed  Google Scholar 

  99. Joussen AM, Poulaki V, Mitsiades N, et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF alpha suppression. FASEB J. 2002;16:438–40.

    CAS  PubMed  Google Scholar 

  100. Kaiser N, Sasson S, Feener EP, et al. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes. 1993;42:80–9.

    Article  CAS  PubMed  Google Scholar 

  101. Kato H, Suzuki H, Tajima S, et al. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens. 1991;9:17–22.

    Article  CAS  PubMed  Google Scholar 

  102. Kawamura H, Kobayashi M, Li Q, et al. Effects of angiotensin II on the pericyte-containing microvasculature of the rat retina. J Physiol. 2004;561:671–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Keough RJ, Dunlop ME, Larkins RG. Effect of inhibition of aldose reductase on glucose flux, diacylglycerol formation, protein kinase C, and phospholipase A2 activation. Metabolism. 1997;46:41–7.

    Article  Google Scholar 

  104. Khan ZA, Farhangkhoee H, Chakrabarti S. Towards newer molecular targets for chronic diabetic complications. Curr Vasc Pharmacol. 2006;4:45–57.

    Article  CAS  PubMed  Google Scholar 

  105. Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol Rev. 2000;52:11–34.

    CAS  PubMed  Google Scholar 

  106. Kiuchi-Saichin Y, Gotoh S, Furuse M, et al. Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. J Am Soc Nephrol. 2002;13:875–86.

    Google Scholar 

  107. Klein R, Klein BE, Moss SE, Wong TY, Hubbard L, Cruickshanks KJ, Palta M. Retinal vascular abnormalities in persons with type 1 diabetes: the Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVIII. Ophthalmology. 2003;110:2118–25.

    Article  PubMed  Google Scholar 

  108. Klein R, Myers CE, Lee KE, Gangnon R, Klein BE. Changes in retinal vessel diameter and incidence and progression of diabetic retinopathy. Arch Ophthalmol. 2012;130:749–55.

    PubMed  PubMed Central  Google Scholar 

  109. Kocak N, Alacacioglu I, Kaynak S, Ozcan MA, Celik O, Yuksel F, Piskin O, Oner H, Saatci AO, Ergin M. Comparison of vitreous and plasma levels of vascular endothelial growth factor, interleukin-6 and hepatocyte growth factor in diabetic and non-diabetic retinal detachment cases. Ann Ophthalmol (Skokie). 2010;42 Spec No:10–4.

    Google Scholar 

  110. Kohner EM. The retinal blood flow in diabetes. Diabetes Metab. 1993;19:401–4.

    CAS  Google Scholar 

  111. Kohner EM, Dollery CT. Fluorescein angiography of the fundus in diabetic retinopathy. Br Med Bull. 1970;26:166–70.

    Article  CAS  PubMed  Google Scholar 

  112. Kohner EM, Hamilton AM, Saunders SJ, Sutcliffe BA, Bulpitt CJ. The retinal blood flow in diabetes. Diabetologia. 1975;11:27–33.

    Article  CAS  PubMed  Google Scholar 

  113. Kohner EM, Henkind P. Correlation of fluorescein angiogram and retinal digest in diabetic retinopathy. Am J Ophthalmol. 1970;69:403–14.

    Article  CAS  PubMed  Google Scholar 

  114. Kohner EM, Patel V, Rassam SM. Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes. 1995;44:603–7.

    Article  CAS  PubMed  Google Scholar 

  115. Kokame GT, de Leon MD, Tanji T. Serous retinal detachment and cystoid macular edema in hypotony maculopathy. Am J Ophthalmol. 2001;131:384–6.

    Article  CAS  PubMed  Google Scholar 

  116. Koya D, Haneda M, Nakagawa H, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J. 2000;14:439–47.

    CAS  PubMed  Google Scholar 

  117. Koya D, King GL. Protein kinase C activation and the development of diabetic complications. Diabetes. 1998;47:859–66.

    Article  CAS  PubMed  Google Scholar 

  118. Kristinsson JK, Gottfredsdotter MS, Stefannson E. Retinal vessel dilatation and elongation precedes diabetic macular oedema. Br J Ophthalmol. 1997;81:274–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Kuiper EJ, Witmer AN, Klaassen I, Oliver N, Goldschmeding R, Schlingemann RO. Differential expression of connective tissue growth factor in microglia and pericytes in the human diabetic retina. Br J Ophthalmol. 2004;88:1082–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Langham ME, Grebe R, Hopkins S, et al. Choroidal blood flow in diabetic retinopathy. Exp Eye Res. 1991;52:167–73.

    Article  CAS  PubMed  Google Scholar 

  121. Lee JH, Lee W, Kwon OH, et al. Cytokine profile of peripheral blood in type 2 diabetes mellitus patients with diabetic retinopathy. Ann Clin Lab Sci. 2008;38:361–7.

    CAS  PubMed  Google Scholar 

  122. Lewis H, Abrams GW, Blumenkranz MS, Campo RV. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloids traction. Ophthalmology. 1992;99:753–9.

    Article  CAS  PubMed  Google Scholar 

  123. Li G, Veenstra AA, Talahalli RR, Wang X, Gubitosi-Klug RA, Sheibani N, Kern TS. Marrow-derived cells regulate the development of early diabetic retinopathy and tactile allodynia in mice. Diabetes. 2012;61:3294–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lieth E, Barber AJ, Xu B, Dice C, Ratz MJ, Tanase D, Strother JM. Glial reactivity and impaired glutamate metabolism in short-term experimental diabetic retinopathy. Diabetes. 1998;47:815–20.

    Article  CAS  PubMed  Google Scholar 

  125. Linsenmeier RA, Braun RD, McRipley MA, et al. Retinal hypoxia in long-term diabetic cats. Invest Ophthalmol Vis Sci. 1998;39:1647–57.

    CAS  PubMed  Google Scholar 

  126. Linskens MH, Harley CB, West MD, Campisi J, Hayflick L. Replicative senescence and cell death. Science. 1995;267:17.

    Article  CAS  PubMed  Google Scholar 

  127. Liu H, Ren JG, Cooper WL, et al. Identification of the antivasopermeability effect of pigment epithelium-derived factor and its active site. Proc Natl Acad Sci U S A. 2004;101:6605–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Ljubimov AV, Burgeson RE, Butkowski RJ, Couchman JR, Zardi L, Ninomiya Y, Sado Y, Huang ZS, Nesburn AB, Kenney MC. Basement membrane abnormalities in human eyes with diabetic retinopathy. J Histochem Cytochem. 1996;44:1469–79.

    Article  CAS  PubMed  Google Scholar 

  129. Lu M, Kuroki M, Amano S, et al. Advanced glycation end products increase retinal vascular endothelial growth factor expression. J Clin Invest. 1998;101:1219–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lu M, Perez VL, Ma N, et al. VEGF increases retinal vascular ICAM-1 expression in vivo. Invest Ophthalmol Vis Sci. 1999;40:1808–12.

    CAS  PubMed  Google Scholar 

  131. Lucis AJ. Atherosclerosis. Nature. 2000;407:233–41.

    Article  Google Scholar 

  132. Matsugi T, Chen Q, Anderson DR. Contractile responses of cultured bovine retinal pericytes to angiotensin II. Arch Ophthalmol. 1997;115:1281–5.

    Article  CAS  PubMed  Google Scholar 

  133. Matter K, Balda MS. Occludin and the functions of tight junctions. Int Rev Cytol. 1999;186:117–46.

    Article  CAS  PubMed  Google Scholar 

  134. Matthews DR, Stratton IM, Aldington SJ, et al. Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69. Arch Ophthalmol. 2004;122:1631–40.

    Article  PubMed  Google Scholar 

  135. McLeod D. Why cotton wool spots should not be regarded as retinal nerve fiber layer infarcts. Br J Ophthalmol. 2005;89:229–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Miller JW, Adamis AP, Aiello LP. Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy. Diabetes Metab Rev. 1997;13:37–50.

    Article  CAS  PubMed  Google Scholar 

  137. Mizutani M, Gerhardinger C, Lorenzi M. Muller cell changes in human diabetic retinopathy. Diabetes. 1998;47:445–9.

    Article  CAS  PubMed  Google Scholar 

  138. Mizutani M, Kern TS, Lorenzi M. Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy. J Clin Invest. 1996;97:2883–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Nagai N, Izumi-Nagai K, Oike Y, et al. Suppression of diabetes-induced retinal inflammation by blocking the angiotensin II type 1 receptor or its downstream nuclear factor-κB pathway. Invest Ophthalmol Vis Sci. 2007;48:4342–50.

    Article  PubMed  Google Scholar 

  140. Nagai N, Noda K, Urano T, et al. Selective suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2005;46:1078–84.

    Article  PubMed  Google Scholar 

  141. Nitta T, Hata M, Gotoh S, et al. Size-selective loosening of the blood-brain barrier in claudin-5 deficient mice. J Cell Biol. 2003;161:653–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ogden TE. The glia of the retina. In: Ryan SJ, Ogden TE, editors. Retina, vol. 1. St. Louis: CV Mosby; 1989. p. 53–6.

    Google Scholar 

  143. Otani A, Takagi H, Oh H, et al. Angiotensin II induces expression of the Tie2 receptor ligand, angiopoietin-2, in bovine retinal endothelial cells. Diabetes. 2001;50:867–75.

    Article  CAS  PubMed  Google Scholar 

  144. Otani A, Takagi H, Suzuma K, Honda Y. Angiotensin II potentiates endothelial growth factor-induced angiogenic activity in retinal microcapillary endothelial cells. Circ Res. 1998;82:619–28.

    Article  CAS  PubMed  Google Scholar 

  145. Ozaki H, Hayashi H, Vinores SA, et al. Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res. 1997;64:505–17.

    Article  CAS  PubMed  Google Scholar 

  146. Padayatti PS, Jiang C, Glomb MA, Uchida K, Nagaraj RH. High concentrations of glucose induce synthesis of argpyrimidine in retinal endothelial cells. Curr Eye Res. 2001;23:106–15.

    Article  CAS  PubMed  Google Scholar 

  147. Pan HZ, Zhang H, Chang D, et al. The change of oxidative stress products in diabetes mellitus and diabetic retinopathy. Br J Ophthalmol. 2008;92:548–51.

    Article  PubMed  Google Scholar 

  148. Patel JI, Tombran-Tink J, Hykin PG, et al. Vitreous and aqueous concentrations of proangiogenic, antiangiogenic factors and other cytokines in diabetic retinopathy patients with macular edema: implications for structural differences in macular profiles. Exp Eye Res. 2006;82:798–806.

    Article  CAS  PubMed  Google Scholar 

  149. Paul SA, Simons JW, Mabjeesh NJ. HIF at the crossroads between ischemia and carcinogenesis. J Cell Physiol. 2004;200:20–30.

    Article  CAS  PubMed  Google Scholar 

  150. Pfeffer BA. Improved methodology for cell culture of human and monkey retinal pigment epithelium. Prog Retinal Res. 1991;10:251.

    Article  Google Scholar 

  151. Pieper GM, Riaz-ul-Haq J. Activation of nuclear factor-kappa B in cultured endothelial cells by increased glucose concentration: prevention by calphostin C. J Cardiovasc Pharmacol. 1997;30:528–32.

    Article  CAS  PubMed  Google Scholar 

  152. Pollock SC, Miller NR. The retinal nerve fiber layer. Int Ophthalmol Clin. 1986;26:201–21.

    Article  CAS  PubMed  Google Scholar 

  153. Portilla D, Dai G, Peters JM, et al. Etomoxir-induced PPARalpha-modulated enzymes protect during acute renal failure. Am J Physiol Renal Physiol. 2000;278:F667–75.

    CAS  PubMed  Google Scholar 

  154. Poulaki V, Qin W, Joussen AM, et al. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. J Clin Invest. 2002;109:805–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Puro DG. Diabetes-induced dysfunction of retinal Muller cells. Trans Am Ophthalmol Soc. 2002;100:339–52.

    PubMed  PubMed Central  Google Scholar 

  156. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Roy MS, Gunkel RD, Podgor MJ. Color vision defects in early diabetic retinopathy. Arch Ophthalmol. 1986;104:225–8.

    Article  CAS  PubMed  Google Scholar 

  158. Roy S, Maiello M, Lorenzi M. Increased expression of basement membrane collagen in human diabetic retinopathy. J Clin Invest. 1994;93:438–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Roy S, Tonkiss J, Roy S. Aging increases retinal vascular lesions characteristic of early diabetic retinopathy. Biogerontology. 2010;11:447–55.

    Article  PubMed  Google Scholar 

  160. Rungger-Brandle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2000;41:1971–80.

    CAS  PubMed  Google Scholar 

  161. Safran M, Kaelin Jr WG. HIF hydroxylation and the mammalian oxygen-sensing pathway. J Clin Invest. 2003;111(6):779–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Saishin Y, Saishin Y, Takahashi K, et al. VEGF-TRAP (R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier. J Cell Physiol. 2003;195:241–8.

    Article  CAS  PubMed  Google Scholar 

  163. Schmetterer L, Wolzt M. Ocular blood flow and associated functional deviations in diabetic retinopathy. Diabetologia. 1999;42:387–405.

    Article  CAS  PubMed  Google Scholar 

  164. Schmidt AM, Hori O, Chen JX, et al. Advanced glycation end-products interacting with their endothelial receptor induce expression of vascular cell adhesion molecule-1 (VCAM-1) in cultured human endothelial cells and in mice: a potential mechanism for the accelerated vasculopathy of diabetes. J Clin Invest. 1995;96:1395–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Schroedl C, McClintock DS, Budinger GR, Chandel NS. Hypoxic but not anoxic stabilization of HIF-1alpha requires mitochondrial reactive oxygen species. Am J Physiol Lung Cell Mol Physiol. 2002;283:L922–31.

    Article  CAS  PubMed  Google Scholar 

  166. Semenza G. Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 2002;64:993–8.

    Article  CAS  PubMed  Google Scholar 

  167. Shakib M, Cunha-Vaz JG. Studies on the permeability of the blood-retinal barrier. IV. Junctional complexes of the retinal vessels and their role in the permeability of the blood-retinal barrier. Exp Eye Res. 1966;5:229–34.

    Article  CAS  PubMed  Google Scholar 

  168. Shin DH, Tsai CS, Parrow KA, et al. Vasoconstrictive effect of topical timolol on human retinal arteries. Graefes Arch Clin Exp Ophthalmol. 1991;229:298–9.

    Article  CAS  PubMed  Google Scholar 

  169. Sigelman J, Ozanics V. Retina. In:Duane’s foundations of clinical ophthalmology. Philadelphia: Lippincott; 1990.

    Google Scholar 

  170. Simo R, Carrasco E, Garcia-Ramirez M, Hernandez C. Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. Curr Diabetes Rev. 2006;2:71–98.

    Article  CAS  PubMed  Google Scholar 

  171. Sinclair SH. Macular retinal capillary hemodynamics in diabetic patients. Ophthalmology. 1991;98:1580–6.

    Article  CAS  PubMed  Google Scholar 

  172. Skovborg F, Nielsen AV, Lauritzen E, Hartkopp O. Diameters of the retinal vessels in diabetic and normal subjects. Diabetes. 1969;18:292–8.

    Article  CAS  PubMed  Google Scholar 

  173. Smelser GK, Ishikawa T, Pei YF. Electron microscopic studies of intra-retinal spaces – diffusion of particulate materials. In: Rohen JW, editor. Structure of the eye, II Symp. Stuttgart: Schattauer-Verlay; 1965. p. 109–21.

    Google Scholar 

  174. Smith RT, Lee CM, Charles HC, et al. Quantification of diabetic macular edema. Arch Ophthalmol. 1987;105:218–22.

    Article  CAS  PubMed  Google Scholar 

  175. Sokol S, Moskowitz A, Skarf B, Evans R, Molitch M, Senior B. Contrast sensitivity in diabetics with and without background retinopathy. Arch Ophthalmol. 1985;103:51–4.

    Article  CAS  PubMed  Google Scholar 

  176. Soulis-Liparota T, Cooper M, Papazoglou D, et al. Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozotocin-induced diabetic rat. Diabetes. 1991;40:1328–34.

    Article  CAS  PubMed  Google Scholar 

  177. Stasek Jr JE, Patterson CE, Garcia JG. Protein kinase C phosphorylates caldesmon 77 and vimentin and enhances albumin permeability across cultured bovine pulmonary artery endothelial cell monolayers. J Cell Physiol. 1992;153:62–75.

    Google Scholar 

  178. Stefansson E. The therapeutic effects of retinal laser treatment and vitrectomy. A theory based on oxygen and vascular physiology. Acta Ophthalmol Scand. 2001;79:435–40.

    Article  CAS  PubMed  Google Scholar 

  179. Stefansson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol. 2006;51:364–80.

    Article  PubMed  Google Scholar 

  180. Stefansson E, Landers 3rd MB, Wolbarsht ML. Increased retinal oxygen supply following pan-retinal photocoagulation and vitrectomy and lensectomy. Trans Am Ophthalmol Soc. 1981;79:307–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Stevenson BR, Keon BH. The tight junction: morphology to molecules. Annu Rev Cell Dev Biol. 1998;14:89–109.

    Article  CAS  PubMed  Google Scholar 

  182. Stitt A, Gardiner TA, Alderson NL, Canning P, Frizzell N, Duffy N, Boyle C, Januszewski AS, Chachich M, Baynes JW, Thorpe SR. The AGE inhibitor pyridoxamine inhibits development of retinopathy in experimental diabetes. Diabetes. 2002;51:2826–32.

    Article  CAS  PubMed  Google Scholar 

  183. Stitt AW, Anderson HR, Gardiner TA, Archer DB. Diabetic retinopathy: quantitative variation in capillary basement membrane thickening in arterial or venous environments. Br J Ophthalmol. 1994;78:133–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Stitt AW, Hughes SJ, Canning P, Lynch O, Cox O, Frizzell N, Thorpe SR, Cotter TG, Curtis TM, Gardiner TA. Substrates modified by advanced glycation end-products cause dysfunction and death in retinal pericytes by reducing survival signals mediated by platelet-derived growth factor. Diabetologia. 2004;47:1735–46.

    Article  CAS  PubMed  Google Scholar 

  185. Stitt AW, Li YM, Gardiner TA, et al. Advanced glycation end products (AGEs) co-localize with AGE receptors in the retinal vasculature of diabetic and of AGE-infused rats. Am J Pathol. 1997;150:523–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Stratton IM, Kohner EM, Aldington SJ, et al. UKPDS 50: risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia. 2001;44:156–63.

    Article  CAS  PubMed  Google Scholar 

  187. Studer RK, Craven PA, DeRubertis FR. Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high-glucose medium. Diabetes. 1993;42:118–26.

    Article  CAS  PubMed  Google Scholar 

  188. Suzuki Y, Ruiz-Ortega M, Lorenzo O, et al. Inflammation and angiotensin II. Int J Biochem Cell Biol. 2003;35:881–900.

    Article  CAS  PubMed  Google Scholar 

  189. Talahalli R, Zarini S, Tang J, Li G, Murphy R, Kern TS, Gubitosi-Klug RA. Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes. J Leukoc Biol. 2013;93:135–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Tamura K, Nyui N, Tamura N, et al. Mechanism of angiotensin II-mediated regulation of fibronectin gene in rat vascular smooth muscle cells. J Biol Chem. 1998;273:26487–96.

    Article  CAS  PubMed  Google Scholar 

  191. Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res. 2011;30:343–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Thornalley PJ. The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life. Biochem J. 1990;269:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Tso MO. Pathological study of cystoid macular oedema. Trans Ophthalmol Soc U K. 1980;100:408–13.

    CAS  PubMed  Google Scholar 

  194. Tso MO. Pathology of cystoid macular edema. Ophthalmology. 1982;89:902–15.

    Article  CAS  PubMed  Google Scholar 

  195. Vinores SA, Van Niel E, Swerrdloff IL, et al. 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.

    Article  CAS  PubMed  Google Scholar 

  196. Wagener HP, Story DTD, Wilder RM. Retinitis in diabetes. N Engl J Med. 1934;211:1131–7.

    Article  Google Scholar 

  197. Wald G, Brown PK. Human rhodopsin. Science. 1958;127:222–6.

    Article  CAS  PubMed  Google Scholar 

  198. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92:5510–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Wang W, Dentler WL, Borchardt RT. VEGF increases BMED monolayer permeability by affecting occludin expression and tight junction assembly. Am J Physiol Heart Circ Physiol. 2001;280:H434–40.

    CAS  PubMed  Google Scholar 

  200. Weinberger D, Fink-Cohen S, Gaton DD, et al. Non-retinovascular leakage in diabetic maculopathy. Br J Ophthalmol. 1995;79:728–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Weiner CM, Booth G, Semenza GL. In vivo expression of mRNAs encoding hypoxia-inducible factor 1. Biochem Biophys Res Commun. 1996;225:485–8.

    Article  Google Scholar 

  202. Wells-Knecht KJ, Zyzak DV, Litchfield JE, et al. Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose. Biochemistry. 1995;34:3702–9.

    Article  CAS  PubMed  Google Scholar 

  203. Wilkinson-Berka J. Angiotensin and diabetic retinopathy. Int J Biochem Cell Biol. 2006;38:752–65.

    Article  CAS  PubMed  Google Scholar 

  204. Williams B, Gallacher B, Patel H, Orme C. Glucose-induced protein kinase C activation regulates vascular permeability factor mRNA expression and peptide production by human vascular smooth muscle cells in vitro. Diabetes. 1997;46:1497–503.

    Article  CAS  PubMed  Google Scholar 

  205. Williamson JR, Chang K, Frangos M, et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes. 1993;42:801–13.

    Article  CAS  PubMed  Google Scholar 

  206. Wise GN, Dollery CT, Henkind P. The retinal circulation. New York: Harper & Row; 1971.

    Google Scholar 

  207. Wong A, Merritt S, Butt AN, et al. Effect of hypoxia on circulating levels of retina-specific messenger RNA in type 2 diabetes mellitus. Ann N Y Acad Sci. 2008;1137:243–52.

    Article  CAS  PubMed  Google Scholar 

  208. Wu HM, Huang Q, Yuan Y, Granger HJ. VEGF induces NO-dependent hyperpermeability in coronary venules. Am J Physiol. 1996;271:H2735–9.

    CAS  PubMed  Google Scholar 

  209. Yamada E. Some structural features of the fovea centralis in the human retina. Arch Ophthalmol. 1969;82:151–9.

    Article  CAS  PubMed  Google Scholar 

  210. Yamagishi SI, Edelstein D, Du XL, Brownlee M. Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes. 2001;50:1491–4.

    Article  CAS  PubMed  Google Scholar 

  211. Yerneni KK, Bai W, Khan BV, et al. Hyperglycemia-induced activation of nuclear transcription factor kappa B in vascular smooth muscle cells. Diabetes. 1999;48:855–64.

    Article  CAS  PubMed  Google Scholar 

  212. Yonemura D, Aoki T, Tsuzuki K. Electroretinogram in diabetic retinopathy. Arch Ophthalmol. 1962;68:19–24.

    Article  CAS  PubMed  Google Scholar 

  213. Zeng HY, Green WR, Tso MO. Microglial activation in human diabetic retinopathy. Arch Ophthalmol. 2008;126:227–32.

    Article  PubMed  Google Scholar 

  214. Zeng XX, Ng YK, Ling EA. Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats. Vis Neurosci. 2000;17:463–71.

    Article  CAS  PubMed  Google Scholar 

  215. Zhang J, Gerhardinger C, Lorenzi M. Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy. Diabetes. 2002;51:3499–504.

    Article  CAS  PubMed  Google Scholar 

  216. Zhang J-Z. Captopril inhibits capillary degeneration the early stages of diabetic retinopathy. Curr Eye Res. 2007;32:883–9.

    Article  PubMed  CAS  Google Scholar 

  217. Zhang SX, Wang JJ, Gao G, et al. Pigment epithelium-derived factor downregulates vascular endothelial growth factor (VEGF) expression and inhibits VEGF-VEGF receptor 2 binding in diabetic retinopathy. J Mol Endocrinol. 2006;37:1–12.

    Article  PubMed  CAS  Google Scholar 

  218. Zinn KM, Marmor MF, editors. The retinal pigment epithelium. Cambridge: Harvard University Press; 1979.

    Google Scholar 

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Stewart, M.W. (2017). The Diabetic Retina: Anatomy and Pathophysiology. In: Diabetic Retinopathy. Adis, Singapore. https://doi.org/10.1007/978-981-10-3509-8_2

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