Advertisement

Molecular Mechanisms of the Inner Blood-Retinal Barrier Transporters

  • Masatoshi Tomi
  • Ken-ichi Hosoya
Part of the Ophthalmology Research book series (OPHRES)

Summary

The inner blood–retinal barrier (inner BRB) forms complex tight junctions of retinal capillary endothelial cells to prevent the free diffusion of substances between the circulating blood and the neural retina. Thus, understanding of the inner BRB transport mechanisms could provide a basis for strategies of drug delivery to the retina. Recent development of several analytical methods has succeeded in showing that the inner BRB is equipped with several membrane transporters such as GLUT1, monocarboxylate transporter 1 (MCT1), creatine transporter (CRT), xCT, L-type amino acid transporter 1 (LAT1), taurine transporter (TauT), equilibrative nucleoside transporter 2 (ENT2), organic anion transporter polypeptide 1a4 (Oatp1a4), multidrug resistance 1a (mdr1a), and ATP-binding cassette transporter G2 (Abcg2). These transporters play essential roles in supplying nutrients to the retina and are responsible for the efflux of neurotransmitter metabolites, toxins, and xenobiotics.

Keywords

Diabetic Retinopathy Organic Anion Neural Retina Goto Kakizaki Organic Anion Transporter Polypeptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This work was supported, in part, by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science and a grant for research on sensory and communicative disorders by the Ministry of Health, Labor, and Welfare, Japan. The authors thank Drs. T. Terasaki, S. Ohtsuki, K. Katayama, T. Kondo, and M. Tachikawa and Messrs. T. Funaki, T. Isobe, H. Abukawa, A. Minamizono, M. Mori, Y. Ohshima, T. Terayama, and K. Nagase for valuable suggestions and technical assistance.

References

  1. 1.
    1. Cunha-Vaz JG. The blood–retinal barriers system. Basic concepts and clinical evaluation. Exp Eye Res 2004;78:715–21.PubMedCrossRefGoogle Scholar
  2. 2.
    2. Hosoya K and Tomi M. Advances in the cell biology of transport via the inner blood–retinal barrier: establishment of cell lines and transport functions. Biol Pharm Bull 2005;28:1–8.PubMedCrossRefGoogle Scholar
  3. 3.
    3. Schnaudigel O. Die vitale farbung mit trypanblau an auge. Graefe Arch Ophthal 1913;86: 93–105.Google Scholar
  4. 4.
    4. Alm A and Törnquist P. The uptake index method applied to studies on the blood–retinal barrier. I. A methodological study. Acta Physiol Scand 1981;113:73–9.PubMedCrossRefGoogle Scholar
  5. 5.
    5. Alm A and Törnquist P. Lactate transport through the blood-retinal and the blood–brain barrier in rats. Ophthalmic Res 1985;17:181–4.PubMedCrossRefGoogle Scholar
  6. 6.
    6. Törnquist P and Alm A. Carrier-mediated transport of amino acids through the blood-retinal and the blood-brain barriers. Graefes Arch Clin Exp Ophthalmol 1986;224:21–5.PubMedCrossRefGoogle Scholar
  7. 7.
    7. Nagase K, Tomi M, Tachikawa M, Hosoya K. Functional and molecular characterization of adenosine transport at the rat inner blood-retinal barrier. Biochim Biophys Acta 2006;1758:13–9.PubMedCrossRefGoogle Scholar
  8. 8.
    8. Katayama K, Ohshima Y, Tomi M, Hosoya K. Application of microdialysis to evaluate the efflux transport of estradiol 17-beta glucuronide across the rat blood-retinal barrier. J Neurosci Methods 2006;156:249–56.PubMedCrossRefGoogle Scholar
  9. 9.
    9. Hjelle JT, Baird-Lambert J, Cardinale G, Specor S, Udenfriend S. Isolated microvessels: the blood-brain barrier in vitro. Proc Natl Acad Sci U S A 1978;75:4544–8.PubMedCrossRefGoogle Scholar
  10. 10.
    10. Betz AL, Goldstein GW. Transport of hexoses, potassium and neutral amino acids into capillaries isolated from bovine retina. Exp Eye Res 1980;30:593–605.PubMedCrossRefGoogle Scholar
  11. 11.
    11. Tomi M, Hosoya K. Application of magnetically isolated rat retinal vascular endothelial cells for the determination of transporter gene expression levels at the inner blood–retinal barrier. J Neurochem 2004;91:1244–8.PubMedCrossRefGoogle Scholar
  12. 12.
    12. Hosoya K, Tomi M, Ohtsuki S, Takanaga H, Ueda M, Yanai N, Obinata M, Terasaki T. Conditionally immortalized retinal capillary endothelial cell lines (TR-iBRB) expressing differentiated endothelial cell functions derived from a transgenic rat. Exp Eye Res 2001;72:163–72.PubMedCrossRefGoogle Scholar
  13. 13.
    13. Ennis SR, Johnson JE, Pautler EL. In situ kinetics of glucose transport across the blood-retinal barrier in normal rats and rats with streptozocin-induced diabetes. Invest Ophthalmol Vis Sci 1982;23:447–56.PubMedGoogle Scholar
  14. 14.
    14. Takata K, Kasahara T, Kasahara M, Ezaki O, Hirano H. Ultracytochemical localization of the erythrocyte/HepG2-type glucose transporter (GLUT1) in cells of the blood-retinal barrier in the rat. Invest Ophthalmol Vis Sci 1992;33:377–83.PubMedGoogle Scholar
  15. 15.
    15. Fernandes R, Suzuki K, Kumagai AK. Inner blood-retinal barrier GLUT1 in long-term diabetic rats: an immunogold electron microscopic study. Invest Ophthalmol Vis Sci 2003;44:3150–4.PubMedCrossRefGoogle Scholar
  16. 16.
    16. Kumagai AK, Vinores SA, Pardridge WM. Pathological upregulation of inner blood-retinal barrier Glut1 glucose transporter expression in diabetes mellitus. Brain Res 1996;706:313–7.PubMedCrossRefGoogle Scholar
  17. 17.
    17. Knott RM, Robertson M, Muckersie E, Forrester JV. Regulation of glucose transporters (GLUT-1 and GLUT-3) in human retinal endothelial cells. Biochem J 1996;318:313–7.PubMedGoogle Scholar
  18. 18.
    18. Tang J, Zhu XW, Lust WD, Kern TS. Retina accumulates more glucose than does the embryologically similar cerebral cortex in diabetic rats. Diabetologia 2000;43:1417–23.PubMedCrossRefGoogle Scholar
  19. 19.
    19. Badr GA, Tang J, Ismail-Beigi F, Kern TS. Diabetes downregulates GLUT1 expression in the retina and its microvessels but not in the cerebral cortex or its microvessels. Diabetes 2000;49:1016–21.PubMedCrossRefGoogle Scholar
  20. 20.
    20. Fernandes R, Carvalho AL, Kumagai A, Seica R, Hosoya K, Terasaki T, Murta J, Pereira P, Faro C. Downregulation of retinal GLUT1 in diabetes by ubiquitinylation. Mol Vis 2004;10:618–28.PubMedGoogle Scholar
  21. 21.
    21. Poitry-Yamate CL, Poitry S, Tsacopoulos M. Lactate released by Müller glial cells is metabolized by photoreceptors from mammalian retina. J Neurosci 1995;15:5179–91.PubMedGoogle Scholar
  22. 22.
    22. Gerhart DZ, Leino RL, Drewes LR. Distribution of monocarboxylate transporters MCT1 and MCT2 in rat retina. Neuroscience 1999;92:367–75.PubMedCrossRefGoogle Scholar
  23. 23.
    23. Hosoya K, Kondo T, Tomi M, Takanaga H, Ohtsuki S, Terasaki T. MCT1-mediated transport of L-lactic acid at the inner blood-retinal barrier: a possible route for delivery of monocarboxylic acid drugs to the retina. Pharm Res 2001;18:1669–76.PubMedCrossRefGoogle Scholar
  24. 24.
    24. Hori K, Katayama N, Kachi S, Kondo M, Kadomatsu K, Usukura J, Muramatsu T, Mori S, Miyake Y. Retinal dysfunction in basigin deficiency. Invest Ophthalmol Vis Sci 2000;41:3128–33.PubMedGoogle Scholar
  25. 25.
    25. Nakashima T, Tomi M, Tachikawa M, Watanabe M, Terasaki T, Hosoya K. Evidence for creatine biosynthesis in Müller glia. Glia 2005;52:47–52.PubMedCrossRefGoogle Scholar
  26. 26.
    26. Nakashima T, Tomi M, Katayama K, Tachikawa M, Watanabe M, Terasaki T, Hosoya K. Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-retinal barrier. J Neurochem 2004;89:1454–61.PubMedCrossRefGoogle Scholar
  27. 27.
    27. Ohia SE, Opere CA, Leday AM. Pharmacological consequences of oxidative stress in ocular tissues. Mutat Res 2005;579:22–36.PubMedGoogle Scholar
  28. 28.
    28. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2000;45:115–34.PubMedCrossRefGoogle Scholar
  29. 29.
    29. Baynes JW and Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1–9.PubMedCrossRefGoogle Scholar
  30. 30.
    30. Hosoya K, Minamizono A, Katayama K, Terasaki T, Tomi M. Vitamin C transport in oxidized form across the rat blood-retinal barrier. Invest Ophthalmol Vis Sci 2004;45:1232–9.PubMedCrossRefGoogle Scholar
  31. 31.
    31. Minamizono A, Tomi M, Hosoya K. Inhibition of dehydroascorbic acid transport across the rat blood-retinal and -brain barriers in experimental diabetes. Biol Pharm Bull 2006;29:2148–50.PubMedCrossRefGoogle Scholar
  32. 32.
    32. Shan XQ, Aw TY, Jones DP. Glutathione-dependent protection against oxidative injury. Pharmacol Ther 1990;47:61–71.PubMedCrossRefGoogle Scholar
  33. 33.
    33. Winkler BS and Giblin FJ. Glutathione oxidation in retina: effects on biochemical and electrical activities. Exp Eye Res 1983;36:287–97.PubMedCrossRefGoogle Scholar
  34. 34.
    34. Wang XF and Cynader MS. Astrocytes provide cysteine to neurons by releasing glutathione. J Neurochem 2000;74:1434–42.PubMedCrossRefGoogle Scholar
  35. 35.
    35. Hosoya K, Saeki S, Terasaki T. Activation of carrier-mediated transport of L-cystine at the blood-brain and blood-retinal barriers in vivo. Microvasc Res 2001;62:136–42.PubMedCrossRefGoogle Scholar
  36. 36.
    36. Tomi M, Hosoya K, Takanaga H, Ohtsuki S, Terasaki T. Induction of xCT gene expression and L-cystine transport activity by diethyl maleate at the inner blood-retinal barrier. Invest Ophthalmol Vis Sci 2002;43:774–9.PubMedGoogle Scholar
  37. 37.
    37. Schutte M and Werner P. Redistribution of glutathione in the ischemic rat retina. Neurosci Lett 1998;246:53–6.PubMedCrossRefGoogle Scholar
  38. 38.
    38. Pow DV and Crook DK. Immunocytochemical evidence for the presence of high levels of reduced glutathione in radial glial cells and horizontal cells in the rabbit retina. Neurosci Lett 1995;193:25–8.PubMedCrossRefGoogle Scholar
  39. 39.
    39. Pow DV. Visualising the activity of the cystine-glutamate antiporter in glial cells using antibodies to aminoadipic acid, a selectively transported substrate. Glia 2001;34:27–38.PubMedCrossRefGoogle Scholar
  40. 40.
    40. Tomi M, Funaki T, Abukawa H, Katayama K, Kondo T, Ohtsuki S, Ueda M, Obinata M, Terasaki T, Hosoya K. Expression and regulation of L-cystine transporter, system xc -, in the newly developed rat retinal Müller cell line (TR-MUL). Glia 2003;43:208–17.PubMedCrossRefGoogle Scholar
  41. 41.
    41. LaNoue KF, Berkich DA, Conway M, Barber AJ, Hu LY, Taylor C, Hutson S. Role of specific aminotransferases in de novo glutamate synthesis and redox shuttling in the retina. J Neurosci Res 2001;66:914–22.PubMedCrossRefGoogle Scholar
  42. 42.
    42. Lieth E, LaNoue KF, Berkich DA, Xu B, Ratz M, Taylor C, Hutson SM. Nitrogen shuttling between neurons and glial cells during glutamate synthesis. J Neurochem 2001;76:1712–23.PubMedCrossRefGoogle Scholar
  43. 43.
    43. Tomi M, Mori M, Tachikawa M, Katayama K, Terasaki T, Hosoya K. L-type amino acid transporter 1-mediated L-leucine transport at the inner blood-retinal barrier. Invest Ophthalmol Vis Sci 2005;46:2522–30.PubMedCrossRefGoogle Scholar
  44. 44.
    44. Kageyama T, Nakamura M, Matsuo A, Yamasaki Y, Takakura Y, Hashida M, Kanai Y, Naito M, Tsuruo T, Minato N, Shimohama S. The 4F2hc/LAT1 complex transports L-DOPA across the blood-brain barrier. Brain Res 2000;879:115–21.PubMedCrossRefGoogle Scholar
  45. 45.
    45. Bodis-Wollner I. Visual electrophysiology in Parkinson's disease: PERG, VEP and visual P300. Clin Electroencephalogr 1997;28:143–7.PubMedGoogle Scholar
  46. 46.
    46. Bhaskar PA, Vanchilingam S, Bhaskar EA, Devaprabhu A, Ganesan RA. Effect of L-dopa on visual evoked potential in patients with Parkinson's disease. Neurology 1986;36:1119–21.PubMedGoogle Scholar
  47. 47.
    47. Averbuch-Heller L, Tusa RJ, Fuhry L, Rottach KG, Ganser GL, Heide W, Buttner U, Leigh RJ. A double-blind controlled study of gabapentin and baclofen as treatment for acquired nystagmus. Ann Neurol 1997;41:818–25.PubMedCrossRefGoogle Scholar
  48. 48.
    48. Kaneko A and Suzuki S. Eye-preservation treatment of retinoblastoma with vitreous seeding. Jpn J Clin Oncol 2003;33:601–7.PubMedCrossRefGoogle Scholar
  49. 49.
    49. Pasantes-Morales H, Klethi J, Ledig M, Mandel P. Free amino acids of chicken and rat retina. Brain Res 1972;41:494–7.PubMedCrossRefGoogle Scholar
  50. 50.
    50. Heller-Stilb B, van Roeyen C, Rascher K, Hartwig HG, Huth A, Seeliger MW, Warskulat U, Haussinger D. Disruption of the taurine transporter gene (taut) leads to retinal degeneration in mice. FASEB J 2002;16:231–3.PubMedGoogle Scholar
  51. 51.
    51. Heinamaki AA. Endogenous synthesis of taurine and GABA in rat ocular tissues. Acta Chem Scand B 1988;42:39–42.PubMedCrossRefGoogle Scholar
  52. 52.
    52. Tomi M, Terayama T, Isobe T, Egami F, Morito A, Kurachi M, Ohtsuki S, Kang YS, Terasaki T, Hosoya K. Function and regulation of taurine transport at the inner blood-retinal barrier. Microvasc Res 2007; 73:100–106.PubMedCrossRefGoogle Scholar
  53. 53.
    53. Pasantes-Morales H, Ochoa de la Paz LD, Sepulveda J, Quesada O. Amino acids as osmolytes in the retina. Neurochem Res 1999;24:1339–46.PubMedCrossRefGoogle Scholar
  54. 54.
    54. Ghiardi GJ, Gidday JM, Roth S. The purine nucleoside adenosine in retinal ischemia-reperfusion injury. Vision Res 1999;39:2519–35.PubMedCrossRefGoogle Scholar
  55. 55.
    55. Lutty GA and McLeod DS. Retinal vascular development and oxygen-induced retinopathy: a role for adenosine. Prog Retin Eye Res 2003;22:95–111.PubMedCrossRefGoogle Scholar
  56. 56.
    56. Baldwin SA, Beal PR, Yao SY, King AE, Cass CE, Young JD. The equilibrative nucleoside transporter family, SLC29. Pflugers Arch 2004;447:735–43.PubMedCrossRefGoogle Scholar
  57. 57.
    57. Yao SY, Ng AM, Sundaram M, Cass CE, Baldwin SA, Young JD. Transport of antiviral 3′-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol Membr Biol 2001;18:161–7.PubMedCrossRefGoogle Scholar
  58. 58.
    58. Engler CB, Sander B, Larsen M, Koefoed P, Parving HH, Lund-Andersen H. Probenecid inhibition of the outward transport of fluorescein across the human blood-retina barrier. Acta Ophthalmol (Copenh) 1994;72:663–7.CrossRefGoogle Scholar
  59. 59.
    59. Gao B, Wenzel A, Grimm C, Vavricka SR, Benke D, Meier PJ, Reme CE. Localization of organic anion transport protein 2 in the apical region of rat retinal pigment epithelium. Invest Ophthalmol Vis Sci 2002;43:510–4.PubMedGoogle Scholar
  60. 60.
    60. Holash JA and Stewart PA. The relationship of astrocyte-like cells to the vessels that contribute to the blood-ocular barriers. Brain Res 1993;629:218–24.PubMedCrossRefGoogle Scholar
  61. 61.
    61. BenEzra D and Maftzir G. Ocular penetration of cyclosporin A. The rabbit eye. Invest Ophthalmol Vis Sci 1990;31:1362–6.PubMedGoogle Scholar
  62. 62.
    62. Shen J, Cross ST, Tang-Liu DD, Welty DF. Evaluation of an immortalized retinal endothelial cell line as an in vitro model for drug transport studies across the blood-retinal barrier. Pharm Res 2003;20:1357–63.PubMedCrossRefGoogle Scholar
  63. 63.
    63. Asashima T, Hori S, Ohtsuki S, Tachikawa M, Watanabe M, Mukai C, Kitagaki S, Miyakoshi N, Terasaki T. ATP-binding cassette transporter G2 mediates the efflux of phototoxins on the luminal membrane of retinal capillary endothelial cells. Pharm Res 2006;23:1235–42.PubMedCrossRefGoogle Scholar
  64. 64.
    64. Boulton M, Rozanowska M, Rozanowski B. Retinal photodamage. J Photochem Photobiol B 2001;64:144–61.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science + Business Media, LLC 2008

Authors and Affiliations

  • Masatoshi Tomi
    • 1
  • Ken-ichi Hosoya
    • 1
  1. 1.Department of PharmaceuticsGraduate School of Medical and Pharmaceutical Sciences, University of ToyamaJapan

Personalised recommendations