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A new hypothesis on mechanisms of retinal vascular permeability in diabetes

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Diabetic Renal-Retinal Syndrome

Abstract

Increased microvascular permeability, a characteristic abnormality in diabetes, is thought to result in microalbuminuria. In this report, Gardner and associates provide evidence that retinal hemorrhages, lipid exudate deposition, and macular edema result from aberrant production of vasoactive agents. Candidate vasoactive factors include histamine and vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Either or both of these substances may be released in excessive amounts after diabetes induced damage to glial cells that support the metabolism of neurons and blood vessels. VEGF/VPF is indicated as having substantive involvement in development of proliferative diabetic retinopathy. Both histamine and VEGF/VPF increase permeability to sodium fluorescein after injection into the vitreous cavity of normal rats. The authors theorize that vasoactive agents may regulate permeability by modifying cellular tight junction proteins of which ZO-1 has been shown to be regulated by histamine. Further, VEGF reduces the amount of occludin, another seven junctional proteins that spans plasma membranes serving as a transmembrane protein permitting cell-to-cell interaction through tight junctions. Diabetic retinopathy may be viewed as a consequence of disturbed cellular metabolism producing vasoactive factors by neurons and/or glia that impact on tight junction proteins. Treatments testing this hypothesis have been designed: a randomized trial of the histamine H1, antagonist, astemizole, to determine whether blocking the effect of histamine will reduce macular edema has begun. As specific antagonists are synthesized, other studios to determine the benefit of interrupting the action of vasodilators on tight junction proteins can be anticipated.

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References

  1. Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 1983; 32(Suppl 2): 64–78.

    PubMed  Google Scholar 

  2. Klein R, Klein BEK, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthalmology 1995; 102: 7–16.

    PubMed  CAS  Google Scholar 

  3. Parving H-H, Viberti GC, Keen H, Christensen JS, Lassen NA. Hemodynamic factors in the genesis of diabetic microangiopathy. Metabolism 1983; 32: 943–949.

    Article  PubMed  CAS  Google Scholar 

  4. Wolbarsht ML, Landers MB, Stefansson E. Vasodilation and the etiology of diabetic retinopathy: a new model. Ophthalmic Surg 1981; 12: 104–107.

    PubMed  CAS  Google Scholar 

  5. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988; 318: 1315–1321.

    Article  PubMed  CAS  Google Scholar 

  6. Newman E, Reichenbach A. The Mueller cell: a functional element of the retina. TIBS 1996; 19: 307–312.

    CAS  Google Scholar 

  7. Zhang Y, Stone J. Role of astrocytes in the control of developing retinal vessels. Invest Ophthalmol Vis Sci 1997; 38: 1653–1656.

    PubMed  CAS  Google Scholar 

  8. Nag S, Takahashi JL, Kilty DW. Role of vascular endothelial growth factor in blood-brain barrier breakdown and angiogenesis in brain trauma. J Neuropathol Exp Neurol 1977; 56: 912–921.

    Article  Google Scholar 

  9. Dvorak HE, Detmar M, Claffey NP, Nagy JA, van de Water L, Senger DR. Vascular permeability factor/vascular endothelial growth factor: an important mediator of angiogenesis in malignancy and inflammation. Int Arch Allergy Immunol 1995; 107: 233–235.

    Article  PubMed  CAS  Google Scholar 

  10. Nowak JZ, Nawrocki J, Maslinski C. Distribution and localization of histamine in bovine and rabbit eye. Agents Actions 1984; 14: 335–340.

    Article  PubMed  CAS  Google Scholar 

  11. Nowak JZ, Nawrocki J. Histamine in the human eye. Ophthalmic Res 1987; 19: 72–75.

    Article  PubMed  CAS  Google Scholar 

  12. Arbones L, Claro E, Picatoste F, Garcia A. [3H] Mepyramine binding to histamine H1 receptors in bovine retina. Biochem Biophys Res Comm 1986; 135: 445–460.

    Article  PubMed  CAS  Google Scholar 

  13. Carroll WJ, Hollis TM, Gardner TW. Retinal histidine decarboxylase activity is elevated in experimental diabetes. Invest Ophthalmol Vis Sci 1988; 29: 1201–1204.

    PubMed  CAS  Google Scholar 

  14. Hollis TM, Gardner TW, Vergis GJ, Kirbo BJ, Butler C, Dull RO, Enea N. Antihistamines reverse blood-ocular barrier permeability in experimental diabetes. J Diabetic Complications 1988; 2: 47–49.

    Article  CAS  Google Scholar 

  15. Enea NA, Hollis TM, Kern JA, Gardner TW. Histamine H 1 receptors mediate increased blood-retinal barrier permeability in experimental diabetes. Arch Ophthalmol 1989; 107: 270–274.

    Article  PubMed  CAS  Google Scholar 

  16. Hollis TM, Campos MJ, Butler C, Gardner TW. Astemizole reduces blood-retinal barrier permeability in experimental diabetes. J Diabetes Complications 1992; 6: 230–235.

    Article  PubMed  CAS  Google Scholar 

  17. Butler C, Hollis TM, Gardner T, Solkol C, Vergis G, Campos M. Histamine receptor antagonists reverse retinal capillary basement membrane thickening in experimental diabetes. Invest Ophthalmol Vis Sci 1988; (Suppl) 29:182.

    Google Scholar 

  18. Bresnick G. Diabetic maculopathy. A critical review highlightling diffuse macular edema. Ophthalmology 1983; 90:1301–1317.

    PubMed  CAS  Google Scholar 

  19. Aiello LP, Avery R, Arrig P et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331:1480–1487.

    Article  PubMed  CAS  Google Scholar 

  20. Murata T, Nakagawa K, Khalil A, Ishibashi T, Inomata H, Sueishi K. The relation between expression of vascular endothelial growth factor and the breakdown of the blood-retinal barrier in diabetic rat retinas. Lab Invest 1996; 74: 819–825.

    PubMed  CAS  Google Scholar 

  21. Lutty GA, McLeod DS, Merges C, Diggs A, Plouet J. Localization of vascular endothelial growth factor in human retina and choroid. Arch Ophthalmol 1996; 114: 971–977.

    Article  PubMed  CAS  Google Scholar 

  22. Amin RH, Frank RN, Kennedy A, Eliot D, Puklin JE, Abrams GW. Vascular endothelial growth factor is present in glial cells of the retina and optic nerve of human subjects with nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 1997; 38: 36–47.

    PubMed  CAS  Google Scholar 

  23. Sone H, Kamakami Y, Okuda Y et al. Ocular vascular endothelial growth factor levels in diabetic rats are elevated before observable retinal proliferative changes. Diabetologia 1197; 40: 726–730.

    Article  Google Scholar 

  24. Aiello LP, Bursell S-E, 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: 1473–1480.

    Article  PubMed  CAS  Google Scholar 

  25. Rapoport SI. Blood-Brain Barrier in Physiology and Medicine. New York, Raven Press. 1976: pp. 63, 108.

    Google Scholar 

  26. Sagaties MJ, Raviola G, Schaeffer S, Miller C. The structural basis of the inner blood-retinal barrier in the eye of Macaca mulatta. Invest Ophthalmol Vis Sci 1987; 28: 2000–2014.

    PubMed  CAS  Google Scholar 

  27. Abbott NJ, Revest PA, Romero IA. Astrocyte-endothelial interaction: physiology andpathology. Neuropathol Appl Neurobiol 1992; 18: 424–433.

    Article  PubMed  CAS  Google Scholar 

  28. Arthur FE, Shivers RR, Bowman PD. Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model. Dev Brain Res 1987; 36: 155–159.

    Article  Google Scholar 

  29. Gardner TW, Lieth E, Khin SA et al. Astrocytes increase barrier function and ZO-1 protein expression in cultured retinal capillary endothelial cells. Invest Ophthalmol Vis Sci, in press.

    Google Scholar 

  30. Masakazu M, Lorenzi M. Increased expression of Bcl-2 in Muller glial cells in human diabetic retinopathy. Diabetes 1997; 46(Suppl 1): 129A.

    Google Scholar 

  31. Lieth E, LaNoue KF, Gardner TW, Barber AJ. Glial glutamate to glutamine conversion is impaired in retinas of diabetic rats. Invest Ophthalmol Vis Sci 1997 1(Suppl) 37: S771.

    Google Scholar 

  32. Vorwerk CK, Lipton SA, Zurakowski D, Hyman BT, Sabel BA, Dreyer EB. Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Invest Ophthalmol Vis Sci 1996; 37: 1618–1624.

    PubMed  CAS  Google Scholar 

  33. Anderson JM, Van Itallie CM. Tight junctions and the molecular basis for regulation of paracel-lular permeability. Am J Physiol 1995; 269: G467–G476.

    PubMed  CAS  Google Scholar 

  34. Anderson JM, Stevenson BR, Jesaitis A, Goodenough DA, Mooseker MS. Characterization of ZO-1, a protein component of the tight junction from mouse liver and Madin-Darby canine kidney cells. J Cell Biol 1988; 106:1141–1149.

    Article  PubMed  CAS  Google Scholar 

  35. Furuse M, Hirase T, Itoh M et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 1993; 123: 1777–1788.

    Article  PubMed  CAS  Google Scholar 

  36. Furuse M, Itoh M, Hirase T et al. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J Cell Biol 1994; 127: 1617–1626.

    Article  PubMed  CAS  Google Scholar 

  37. Lum H, Malik AB. Mechanisms of increased endothelial permeability. Can J Physiol Pharmacol 1996; 74: 787–800.

    PubMed  CAS  Google Scholar 

  38. Gardner TW, Lesher T, Khin S, Vu C, Barber A, Brennan WA Jr. Histamine reduces ZO-1 tight junction protein expression in cultured retinal capillary endothelial cells. Biochem J 1996; 320:717–721.

    PubMed  CAS  Google Scholar 

  39. Feng D, Nagy JA, Hipp J, Dvorak HF, Dvorak AM. Vesiculo-vacuolar organelles and the regulation of venule permeability to macromolecules by vascular permeability factor, histamine, and serotonin. J Exp Med 1996; 183: 1981–1986.

    Article  PubMed  CAS  Google Scholar 

  40. Wong V, Gumbiner B. A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J Cell Biol 1997; 136: 399–409.

    Article  PubMed  CAS  Google Scholar 

  41. Chakrabarti S, Sima AAF. Alteration of endothelin-1 (ET-1) and ET-3 mRNA and immunore-active protein in the retina of chronically diabetic BB/W rats. Diabetes 1997; 46(Suppl 1): 71A.

    Google Scholar 

  42. Meyer-Franke A, Kaplan MR, Pfrieger FW, Barres BA. Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 1995; 15: 805–819.

    Article  PubMed  CAS  Google Scholar 

  43. Koyami Y, Kimura Y, Baba K. Induction of glutamine synthetase by L-alpha aminoadipate in developmental stages of cultured astrocytes. Neurosci Lett 1997; 223: 65–68.

    Article  Google Scholar 

  44. Bresnick GH. Diabetic retinopathy viewed as a neurosensory disorder. Arch Ophthalmol 1986; 104: 989–990.

    Article  PubMed  CAS  Google Scholar 

  45. Markle RA, Hollis TM, Cosgarea A. Renal histamine increases in the streptozotocin-diabetic rat. Exp Mol Pathol 1986; 44: 21–28.

    Article  PubMed  CAS  Google Scholar 

  46. Ichikawa I, Brenner BM. Mechanisms of action of histamine and histamine antagonists on the glomerular microcirculation in rats. Circ Res 1979; 45: 737–745.

    Article  PubMed  CAS  Google Scholar 

  47. Iijima K, Yoshikawa N, Connolly DT. Expression of vascular endothelial growth factor by mesangial cells. J Am Soc Nephrol 1992; 3: 514 (Abstract).

    Google Scholar 

  48. Simon M, Grone H-J, Johren O, Plate KH, Fuchs E, Risau W. Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am J Physiol 1995; 268: F240–F250.

    PubMed  CAS  Google Scholar 

  49. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977–986.

    Article  Google Scholar 

  50. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. The second report of Diabetic Retinopathy Study Findings. Ophthalmology 1978; 85: 82–105.

    Google Scholar 

  51. Early Treatment Diabetic Retinopathy Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study. Report No. 1. Arch Ophthalmol 1985; 103: 1796–1806.

    Article  Google Scholar 

  52. Stefansson E, Machemer R, deJuan E Jr., McCuen BW 2nd. Retinal oxygenation and laser treatment in patients with diabetic retinopathy. Am J Ophthalmol 1992; 113: 36–38.

    PubMed  CAS  Google Scholar 

  53. Weiter JJ, Zuckerman R. The influence of the photoreceptor-retinal pigment epithelium complex. An explanation for the beneficial effects of photocoagulation. Ophthalmology 1980; 87:1133–1139.

    PubMed  CAS  Google Scholar 

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Authors
  1. Thomas W. Gardner
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  2. Erich Lieth
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  3. David A. Antonetti
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  4. Alistair J. Barber
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Editor information

Editors and Affiliations

  1. Department of Medicine, State University of New York, Health Science Center at Brooklyn, Brooklyn, NY, USA

    Eli A. Friedman M.D. (Distinguished Teaching Professor) (Distinguished Teaching Professor)

  2. College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Francis A. L’Esperance Jr. M.D. (Clinical Professor of Opthalmology) (Clinical Professor of Opthalmology)

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© 1998 Springer Science+Business Media Dordrecht

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Gardner, T.W., Lieth, E., Antonetti, D.A., Barber, A.J. (1998). A new hypothesis on mechanisms of retinal vascular permeability in diabetes. In: Friedman, E.A., L’Esperance, F.A. (eds) Diabetic Renal-Retinal Syndrome. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-4962-4_11

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  • DOI: https://doi.org/10.1007/978-94-011-4962-4_11

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-6083-7

  • Online ISBN: 978-94-011-4962-4

  • eBook Packages: Springer Book Archive

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