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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

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Summary

Light-microscopic immunohistochemical staining for albumin has been used to localize sites of blood-retinal barrier (BRB) breakdown in ocular disorders, but the mechanism for BRB compromise cannot be resolved at this level. Using eyes up to 2 days post-mortem from normal patients or from patients with diabetic retinopathy, or other disorders known to cause BRB failure, electron-microscopic immunocytochemistry reveals focal breakdown of the inner BRB, comprised of the retinal vascular endothelium (RVE), which appears to be mediated by diffuse permeation of the RVE cells and by vesicular transport. Permeation of the retinal pigmented epithelial (RPE) cells that comprise the outer BRB also occurs, but there is no evidence of opening of tight junctions between RVE or RPE in any of the disorders evaluated. Increased aldose reductase (AR) expression in the RVE and RPE cells of diabetics as well as in the perivascular retinal astrocytes, which interact with RVE cells to establish the inner BRB, suggests that AR activity and the subsequent intracellular accumulation of sorbitol in these cell types may impair the function of the BRB in diabetes.

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References

  • Arthur, F. E., Shivers, R. R. & Bowman, P. D. (1987) Astrocyte-mediated induction of tight junctions in brain capillary endothelium: an efficient in vitro model. Dev. Brain Res. 36, 155–59.

    Google Scholar 

  • Blair, N. P., Tso, M. O. M. & Dodge, J. T. (1984) Pathologic studies of the blood-retinal barrier in the spontaneously diabetic BB rats. Invest. Ophthalmol. Vis. Sci. 25, 302–11.

    Google Scholar 

  • Brightman, M. W. (1989) The anatomic basis of the blood-brain barrier. In Implications of the Blood-Brain Barrier and Its Manipulation, vol. 1 (edited by NeuweitE. A. J.), pp. 53–83. New York: Plenum.

    Google Scholar 

  • Bradbury, W. B. (1984) The structure and function of the blood-brain barrier. Fed. Proc. 43, 186–90.

    Google Scholar 

  • Caldwell, R. B., Slapnick, S. M. & Mclaughlin, B. J. (1985) Lanthanum and freeze-fracture studies of retinal pigment epithelial cell junctions in the streptozotocin diabetic rat. Curr. Eye Res. 4, 215–27.

    Google Scholar 

  • Casley-Smith, J. R. (1969) A electron microscopical demonstration of the permeability of cerebral and retinal capillaries to ions. Experientia 25, 845–47.

    Google Scholar 

  • Cervós-Navarro, J., Kannuki, S. & Nakagawa, Y. (1988) Blood-brain barrier (BBB). Review from morphological aspect. Histol. Histopath. 3, 203–13.

    Google Scholar 

  • Cunha-Vaz, J. G., Mota, C. C., Leite, E. C., Abreu, J. R. & Ruas, M. A. (1985) Effect of sulindac on the permeability of the blood-retinal barrier in early diabetic retinopathy. Arch. Ophthalmol. 103, 1307–11.

    Google Scholar 

  • Essner, E. (1987) Role of vesicular transport in breakdown of the blood-retinal barrier. Lab. Invest. 56, 457–60.

    Google Scholar 

  • Essner, E., Pino, R. M. & Griewski, R. A. (1979) Permeability of retinal capillaries in rats with inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 18, 859–63.

    Google Scholar 

  • Essner, E., Pino, R. M. & Griewski, R. A. (1980) Breakdown of blood-retinal barrier in RCS rats with inherited retinal degeneration. Lab. Invest. 43, 418–26.

    Google Scholar 

  • Frank, R. N., Keirn, R. J., Kennedy, A. & Frank, K. W. (1983) Galactose-induced retinal capillary basement membrane thickening: prevention by sorbinil. Invest. Ophthalmol. Vis. Sci. 24, 1519–23.

    Google Scholar 

  • Gabbay, K. H. (1973) The sorbitol pathway and the complications of diabetes. N. Engl. J. Med. 288, 831–36.

    Google Scholar 

  • Ishibashi, T., Tanaka, K. & Taniguchi, Y. (1980) Disruption of blood-retinal barrier in experimental diabetic rats: an electron microscopic study. Exp. Eye Res. 30, 401–10.

    Google Scholar 

  • Janzer, R. C. & Raff, M. C. (1987) Astrocytes induce blood-brain barrier properties in endothelial cells. Nature 325, 253–7.

    Google Scholar 

  • Jones, C. W., Cunha-Vaz, J., Zweing, K. O. & Stein, M. (1979) Kinetic vitreous fluorophotometry in experimental diabetes. Arch. Ophthalmol. 97, 1941–3.

    Google Scholar 

  • Jones, C. W., Cunha-Vaz, J. G. & Rusin, M. M. (1982) Vitreous fluorophotometry in the alloxan and streptozotocintreated rat. Arch. Ophthalmol. 100, 1141–5.

    Google Scholar 

  • Kador, P. F., Akagi, Y., Takahashi, Y., Ikebe, H., Wyman, M. & Kinoshita, J. H. (1990a) Prevention of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by aldose reductase inhibitors. Arch. Ophthalmol. 108, 1301–9.

    Google Scholar 

  • Kador, P. F., Akagi, Y., Takahashi, Y., Wyman, M. & Kinoshita, J. H. (1990b) Effect of aldose reductase inhibitors on retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs. In Diabetes Mellitus and Its Complications (edited by BrownleeM. & SherwoodL. M.), pp. 43–57. Philadelphia: Hanley & Belfus.

    Google Scholar 

  • Kenking, P., Bellhorn, R. W. & Schall, B. (1980) Retinal edema: postulated mechanism(s). In The Blood-Retinal Barriers (edited by Cunha-VazJ. G.), pp. 251–68. New York: Plenum.

    Google Scholar 

  • Kinoshita, J. H. & Nishimura, C. (1988) The involvement of aldose reductase in diabetic complications. Diabetes Metab. Rev. 4, 323–37.

    Google Scholar 

  • Kitagawa, K., Matsumoto, M., Tagaya, M., Ueda, H., Oku, N., Kuwabara, K., Ohtsuki, T., Handa, N., Kimura, K. & Kamada, T. (1991) Temporal profile of serum albumin extravasation following cerebral ischemia in a newly established reproducible gerbil model for vasogenic brain edema: a combined immunohistochemical and dye tracer analysis. Acta Neuropathol. 82, 164–71.

    Google Scholar 

  • Krupin, T., Waltman, S. R., Scharp, D. W., Oestrich, C., Feldman, S., Becker, B., Ballinger, W. & Lacy, P. (1979) Ocular fluorophotometry in streptozotocin diabetes mellitus in the rat: effect of pancreatic islet isografts. Invest. Ophthalmol. Vis. Sci. 18, 1185–90.

    Google Scholar 

  • Lightman, S., Rechthand, E., Terubayashi, H., Palestine, A., Rapoport, S. & Kador, P. (1987) Permeability changes in blood-retinal barrier of galactosemic rats are prevented by aldose reductase inhibitors. Diabetes 36, 1271–5.

    Google Scholar 

  • Long, D. M. (1970) Capillary ultrastructure of the blood-brain barrier in human malignant brain tumors. J. Neurosurg. 32, 127–44.

    Google Scholar 

  • Ludvigson, M. A. & Sorenson, R. L. (1980) Immunohistochemical localization of aldose reductase. I. Enzyme purification and antibody preparation - localization in peripheral nerve, artery, and testis. Diabetes 29, 438–49.

    Google Scholar 

  • Mihály, A. & Bozóky, B. (1984) Immunohistochemical localization of extravasated serum albumin in the hippocampus of human subjects with partial and generalized epilepsies and epileptiform convulsions. Acta Neuropathol. 65, 25–34.

    Google Scholar 

  • Milam, A. H. & Jacobson, S. G. (1990) Photoreceptor rosettes with blue cone opsin immunoreactivity in retinitis pigmentosa. Ophthalmology 97, 1620–31.

    Google Scholar 

  • Neuhaus, J., Risau, W. & Wolburg, H. (1991) Induction of blood-brain barrier characteristics in bovine brain endothelial cells by rat astroglial cells in transfilter culture. Ann. N. Y. Acad. Sci. 633, 578–80.

    Google Scholar 

  • Patz, A., Schaltz, H., Berkow, J. W., Gittelsohm, A. M. & Ticho, U. (1973) Macular edema: an overlooked complication of diabetic retinopathy. Trans. Am. Acad. Ophthalmol. Otolaryngol. 77, 34–42.

    Google Scholar 

  • Poduslo, J. F. & Curran, G. L. (1992) Increased permeability across the blood-nerve barrier of albumin glycated in vitro and in vivo from patients with diabetic polyneuropathy. Proc. Natl Acad. Sci. USA 89, 2218–22.

    Google Scholar 

  • Robison, W. G. Jr, Kador, P. F. & Kinoshita, J. H. (1983) Retinal capillaries: basement membrane thickening by galactosemia prevented with aldose reductase inhibitor. Science 221, 1177–9.

    Google Scholar 

  • Robison, W. G. Jr, Nagata, M., Laver, N., Hohman, T. C. & Kinoshita, J. H. (1989) Diabetic-like retinopathy in rats prevented with an aldose reductase inhibitor. Invest. Ophthalmol. Vis. Sci. 30, 2285–92.

    Google Scholar 

  • Schmidt-Kastner, R., Szymas, J. & Hossmann, K-A. (1990) Immunohistochemical study of glial reaction and serumprotein extravasation in relation to neuronal damage in rat hippocampus after ischemia. Neuroscience 38, 527–40.

    Google Scholar 

  • Shakib, M. & Cunha-Vaz, J. G. (1966) 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. 5, 229–34.

    Google Scholar 

  • Shivers, R. R., Betz, A. L. & Goldstein, G. W. (1984) Isolated rat brain capillaries possess intact, structurally complex, interendothelial tight junctions; freeze-fracture verification of tight junction integrity. Brain Res. 324, 313–22.

    Google Scholar 

  • Smardo, F. L., Jr, Burg, M. B. & Garcia-Perez, A. (1992) Kidney aldose reductase gene transcription is osmotically regulated. Am. J. Physiol. 262, C776–82.

    Google Scholar 

  • Stewart, P. A. & Wiley, M. J. (1981) Developing nervous tissue induces formation of blood-brain barrier characteristics in invading endothelial cells: a study using quail-chick transplantation chimeras. Dev. Biol. 84, 184–92.

    Google Scholar 

  • Tao-Cheng, J-H., Nagy, Z., & Brightman, M. W. (1987) Tight junctions of cerebral endothelium in vitro are enhanced in the company of glia. J. Neurosci. 7, 3293–9.

    Google Scholar 

  • Tontsch, U. & Bauer, H-C. (1991) Glial cells and neurons induce blood-brain barrier related enzymes in cultured cerebral endothelial cells. Brain Res. 549, 247–53.

    Google Scholar 

  • Tso, M. O. M., Cunha-Vaz, J. G., Shih, C-Y. & Jones, C. W. (1980) Clinicopathologic study of blood-retinal barrier in experimental diabetes mellitus. Arch. Ophthalmol. 98, 2032–40.

    Google Scholar 

  • Vine, A. K., Kisly, A. M., Betz, A. L. & Howatt, W. F. (1984) Vitreous fluorophotometry in rats with streptozotocin-induced diabetes. Arch. Ophthalmol. 102, 1083–5.

    Google Scholar 

  • Vinores, S. A. & Campochiaro, P. A. (1989) Prevention or moderation of some ultrastructural changes in the RPE and retina of galactosemic rats by aldose reductase inhibition. Exp. Eye Res. 49, 495–510.

    Google Scholar 

  • Vinores, S. A., Herman, M. M., Rubinstein, L. J. & Marangos, P. J. (1984) Electron microscopic localization of neuronspecific enolase in rat and mouse brain. J. Histochem. Cytochem. 32, 1295–302.

    Google Scholar 

  • Vinores, S. A., Campochiaro, P. A., Williams, E. H., May, E. E., Green, W. R. & Sorenson, R. L. (1988) Aldose reductase expression in human diabetic retina and retinal pigment epithelium. Diabetes 37, 1658–64.

    Google Scholar 

  • Vinores, S. A., Gadegbeku, C., Campochiaro, P. A., & Green, W. R. (1989) Immunohistochemical localization of blood-retinal barrier breakdown in human diabetics. Am. J. Pathol. 134, 231–5.

    Google Scholar 

  • Vinores, S. A., Campochiaro, P. A., Lee, A., Mcgehee, R., Gadegbeku, C. & Green, W. R. (1990a) Localization of blood-retinal barrier breakdown in human pathologic specimens by immunohistochemical staining for albumin. Lab. Invest. 62, 742–50.

    Google Scholar 

  • Vinores, S. A., Mcgehee, R., Lee, A., Gadegbeku, C. & Campochiaro, P. A. (1990b) Ultrastructural localization of blood-retinal barrier breakdown in diabetic and galactosemic rats. J. Histochem. Cytochem. 38, 1341–52.

    Google Scholar 

  • Vinores, S. A., Mcgehee, R., Lee, A., Gadegbeku, C., Orman, W. & Campochiaro, P. A. (1990c) Ultrastructural localization of blood-retinal barrier breakdown sites in diabetic and galactosemic rats and in human diabetics. Invest. Ophthalmol. Vis. Sci. 31 (4), 196.

    Google Scholar 

  • Vinores, S. A., Sen, H. & Campochiaro, P. A. (1992) An adenosine agonist and prostaglandin E1 cause breakdown of the blood-retinal barrier by opening tight junctions between vascular endothelial cells. Invest. Ophthalmol. Vis. Sci. 33, 1870–8.

    Google Scholar 

  • Vlassara, H. (1991) Cell-mediated interactions of glucose-modified proteins and the vascular wall in vasculopathy of diabetes and aging. In Proceedings of the Third International Conference: The Use of Human Cells, Tissues and Organs in Research (edited by Torgerson, L. D., Strickler, S., Sheridan, W. & Lucaccioni, B.), pp. 94–95. Philadelphia: The National Disease Research Interchange.

    Google Scholar 

  • Williams, S. K., Devenny, J. J. & Bitensky, M. W. (1981) Micropinocytotic ingestion of glycosylated albumin by isolated microvessels: possible role in pathogenesis of diabetic microangiopathy. Proc. Natl Acad. Sci. USA 78, 2393–7.

    Google Scholar 

  • Williamson, J. R., Chang, K., Tilton, R. G., Prater, C., Jeffrey, J. R., Weigel, C., Sherman, W. R., Eades, D. M. & Kilo, C. (1987) Increased vascular permeability in spontaneously diabetic BB/W rats and in rats with mild versus severe streptozotocin-induced diabetes: prevention by aldose reductase inhibitors and castration. Diabetes 36, 813–21.

    Google Scholar 

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Authors and Affiliations

  1. Department of Ophthalmology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, 21287, Baltimore, MD, USA

    Stanley A. Vinores Ph.D & Peter A. Campochiaro

  2. Department of Neuroscience, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, 21287, Baltimore, MD, USA

    Peter A. Campochiaro

  3. Department of Ophthalmology, University of Virginia School of Medicine, 22908, Charlottesville, VA, USA

    Stanley A. Vinores Ph.D, Ellen Van Niel, Jason L. Swerdloff & Peter A. Campochiaro

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  1. Stanley A. Vinores Ph.D
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Vinores, S.A., Van Niel, E., Swerdloff, J.L. et al. 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 25, 648–663 (1993). https://doi.org/10.1007/BF00157879

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  • DOI: https://doi.org/10.1007/BF00157879

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