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. 2000;9(5):243–248. doi: 10.1080/09629350020025764

Effect of cyclosporin-A on the blood--retinal barrier permeability in streptozotocin-induced diabetes.

A Carmo 1, J G Cunha-Vaz 1, A P Carvalho 1, M C Lopes 1
PMCID: PMC1781767  PMID: 11200365

Abstract

BACKGROUND: Our previous results showed that in retinas from streptozotocin (STZ)-induced diabetic rats there is an increased level of interleukin-1beta (IL-1beta). This cytokine may be involved in the expression of the inducible isoform of the nitric oxide synthase (iNOS), with consequent synthesis of large amounts of NO and blood-retinal barrier (BRB) breakdown. AIMS: The aim of this work was to examine whether the administration of cyclosporin-A (Cs-A) to STZ-induced diabetic rats inhibits the synthesis of IL-1beta and the expression of the inducible proteins, iNOS and cyclo-oxygenase-2 (COX-2) in retinal cells, and whether the activity of these proteins contribute to BRB breakdown. METHODS: The level of IL-1beta was evaluated by ELISA and the NO production by L-[3H]-citrulline formation. Expression of iNOS and COX-2 proteins was determined by two methods, western blot and immunohistochemistry. The permeability of the BRB was assessed by quantification of the vitreous protein. RESULTS AND DISCUSSION: Our results indicated that the levels of IL-1beta and NO in retinas from Cs-A-treated diabetic rats are significantly reduced, as compared to that in non-treated diabetic rats. The treatment of diabetic rats with Cs-A also significantly inhibited the expression of the inducible proteins, iNOS and COX-2. The evaluation of the vitreous protein content revealed that Cs-A also reduces the BRB permeability. Taken together, these results suggest that the increased production of the inflammatory mediators, IL-1beta and NO, in diabetes may affect the BRB permeability and therefore contribute to the development of diabetic retinopathy.

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Selected References

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  1. Bamforth S. D., Lightman S. L., Greenwood J. Ultrastructural analysis of interleukin-1 beta-induced leukocyte recruitment to the rat retina. Invest Ophthalmol Vis Sci. 1997 Jan;38(1):25–35. [PubMed] [Google Scholar]
  2. Berkowitz B. A., Roberto K. A., Penn J. S. The vitreous protein concentration is increased prior to neovascularization in experimental ROP. Curr Eye Res. 1998 Feb;17(2):218–221. doi: 10.1076/ceyr.17.2.218.5604. [DOI] [PubMed] [Google Scholar]
  3. Bone A. J., Walker R., Varey A. M., Cooke A., Baird J. D. Effect of cyclosporin on pancreatic events and development of diabetes in BB/Edinburgh rats. Diabetes. 1990 Apr;39(4):508–514. doi: 10.2337/diab.39.4.508. [DOI] [PubMed] [Google Scholar]
  4. Carmo A., Cunha-Vaz J. G., Carvalho A. P., Lopes M. C. L-arginine transport in retinas from streptozotocin diabetic rats: correlation with the level of IL-1 beta and NO synthase activity. Vision Res. 1999 Nov;39(23):3817–3823. doi: 10.1016/s0042-6989(99)00117-0. [DOI] [PubMed] [Google Scholar]
  5. Claudio L., Martiney J. A., Brosnan C. F. Ultrastructural studies of the blood-retina barrier after exposure to interleukin-1 beta or tumor necrosis factor-alpha. Lab Invest. 1994 Jun;70(6):850–861. [PubMed] [Google Scholar]
  6. Cunha-Vaz J., Faria de Abreu J. R., Campos A. J. Early breakdown of the blood-retinal barrier in diabetes. Br J Ophthalmol. 1975 Nov;59(11):649–656. doi: 10.1136/bjo.59.11.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dawson J., Hurtenbach U., MacKenzie A. Cyclosporin A inhibits the in vivo production of interleukin-1beta and tumour necrosis factor alpha, but not interleukin-6, by a T-cell-independent mechanism. Cytokine. 1996 Dec;8(12):882–888. doi: 10.1006/cyto.1996.0118. [DOI] [PubMed] [Google Scholar]
  8. Do carmo A., Ramos P., Reis A., Proença R., Cunha-vaz J. G. Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes. Exp Eye Res. 1998 Nov;67(5):569–575. doi: 10.1006/exer.1998.0546. [DOI] [PubMed] [Google Scholar]
  9. Kunz D., Walker G., Eberhardt W., Nitsch D., Pfeilschifter J. Interleukin 1 beta-induced expression of nitric oxide synthase in rat renal mesangial cells is suppressed by cyclosporin A. Biochem Biophys Res Commun. 1995 Nov 13;216(2):438–446. doi: 10.1006/bbrc.1995.2642. [DOI] [PubMed] [Google Scholar]
  10. Lipman R. M., Epstein R. J., Hendricks R. L. Suppression of corneal neovascularization with cyclosporine. Arch Ophthalmol. 1992 Mar;110(3):405–407. doi: 10.1001/archopht.1992.01080150103037. [DOI] [PubMed] [Google Scholar]
  11. Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia. 1996 Sep;39(9):1005–1029. doi: 10.1007/BF00400649. [DOI] [PubMed] [Google Scholar]
  12. Martin M., Neumann D., Hoff T., Resch K., DeWitt D. L., Goppelt-Struebe M. Interleukin-1-induced cyclooxygenase 2 expression is suppressed by cyclosporin A in rat mesangial cells. Kidney Int. 1994 Jan;45(1):150–158. doi: 10.1038/ki.1994.18. [DOI] [PubMed] [Google Scholar]
  13. McDaniel M. L., Kwon G., Hill J. R., Marshall C. A., Corbett J. A. Cytokines and nitric oxide in islet inflammation and diabetes. Proc Soc Exp Biol Med. 1996 Jan;211(1):24–32. doi: 10.3181/00379727-211-43950d. [DOI] [PubMed] [Google Scholar]
  14. Rabinovitch A., Suarez-Pinzon W. L. Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol. 1998 Apr 15;55(8):1139–1149. doi: 10.1016/s0006-2952(97)00492-9. [DOI] [PubMed] [Google Scholar]
  15. Sjöholm A. Aspects of the involvement of interleukin-1 and nitric oxide in the pathogenesis of insulin-dependent diabetes mellitus. Cell Death Differ. 1998 Jun;5(6):461–468. doi: 10.1038/sj.cdd.4400379. [DOI] [PubMed] [Google Scholar]
  16. Tetsuka T., Baier L. D., Morrison A. R. Antioxidants inhibit interleukin-1-induced cyclooxygenase and nitric-oxide synthase expression in rat mesangial cells. Evidence for post-transcriptional regulation. J Biol Chem. 1996 May 17;271(20):11689–11693. doi: 10.1074/jbc.271.20.11689. [DOI] [PubMed] [Google Scholar]
  17. Vinores S. A., Van Niel E., Swerdloff J. L., Campochiaro P. A. 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 Dec;57(6):723–735. doi: 10.1006/exer.1993.1180. [DOI] [PubMed] [Google Scholar]
  18. Welsh M., Welsh N., Bendtzen K., Mares J., Strandell E., Oberg C., Sandler S. Comparison of mRNA contents of interleukin-1 beta and nitric oxide synthase in pancreatic islets isolated from female and male nonobese diabetic mice. Diabetologia. 1995 Feb;38(2):153–160. doi: 10.1007/BF00400089. [DOI] [PubMed] [Google Scholar]
  19. do Carmo A., Lopes C., Santos M., Proença R., Cunha-Vaz J., Carvalho A. P. Nitric oxide synthase activity and L-arginine metabolism in the retinas from streptozotocin-induced diabetic rats. Gen Pharmacol. 1998 Mar;30(3):319–324. doi: 10.1016/s0306-3623(97)00363-7. [DOI] [PubMed] [Google Scholar]

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