Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

  • Authors:
    • Viktor R. Drel
    • Pal Pacher
    • Tayyeba K. Ali
    • Jeho Shin
    • Ulrich Julius
    • Azza B. El-Remessy
    • Irina G. Obrosova
  • View Affiliations

  • Published online on: June 1, 2008     https://doi.org/10.3892/ijmm.21.6.667
  • Pages: 667-676
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Abstract

This study was aimed at evaluating the potent and specific aldose reductase inhibitor fidarestat, on diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis. Control and streptozotocin-diabetic rats were treated with or without fidarestat (16 mg kg-1d-1) for 10 weeks after an initial 2-week period without treatment. Lens changes were evaluated by indirect ophthalmoscopy and portable slit lamp. Nitrotyrosine, poly(ADP-ribose), and glial fibrillary acidic protein expression were assessed by immunohistochemistry. The rate of apoptosis was quantified in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. To dissect the effects of high glucose exposure in retinal microvascular cells, primary bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without fidarestat (10 μM) for 3-14 days. Apoptosis was assessed by TUNEL assay, nitrotyrosine and poly(ADP-ribose) by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Fidarestat treatment prevented diabetic cataract formation and counteracted retinal nitrosative stress, and poly(ADP-ribose) polymerase activation, as well as glial activation. The number of TUNEL-positive nuclei (mean ± SEM) was increased approximately 4-fold in diabetic rats vs. controls (207±33 vs. 49±4, p<0.01), and this increase was partially prevented by fidarestat (106±34, p<0.05 vs. untreated diabetic group). The apoptotic cell number increased with the prolongation of exposure of both pericytes and endothelial cells to high glucose levels. Fidarestat counteracted nitrotyrosine and poly(ADP-ribose) accumulation and apoptosis in both cell types. Antiapoptotic effect of fidarestat in high glucose-exposed retinal pericytes was not associated with the inhibition of Bax or increase in Bcl-2 expression. In conclusion, the findings, i) support an important role for aldose reductase in diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis, and ii) provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for the prevention and treatment of diabetic ocular complications.

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June 2008
Volume 21 Issue 6

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Drel VR, Pacher P, Ali TK, Shin J, Julius U, El-Remessy AB and Obrosova IG: Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis. Int J Mol Med 21: 667-676, 2008.
APA
Drel, V.R., Pacher, P., Ali, T.K., Shin, J., Julius, U., El-Remessy, A.B., & Obrosova, I.G. (2008). Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis. International Journal of Molecular Medicine, 21, 667-676. https://doi.org/10.3892/ijmm.21.6.667
MLA
Drel, V. R., Pacher, P., Ali, T. K., Shin, J., Julius, U., El-Remessy, A. B., Obrosova, I. G."Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis". International Journal of Molecular Medicine 21.6 (2008): 667-676.
Chicago
Drel, V. R., Pacher, P., Ali, T. K., Shin, J., Julius, U., El-Remessy, A. B., Obrosova, I. G."Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis". International Journal of Molecular Medicine 21, no. 6 (2008): 667-676. https://doi.org/10.3892/ijmm.21.6.667