Na+/H+-exchanger-1 inhibition counteracts diabetic cataract formation and retinal oxidative-nitrative stress and apoptosis

  • Authors:
    • Sergey Lupachyk
    • Roman Stavniichuk
    • Julia I. Komissarenko
    • Viktor R. Drel
    • Alexander A. Obrosov
    • Azza B. El-Remessy
    • Pal Pacher
    • Irina G. Obrosova
  • View Affiliations

  • Published online on: March 7, 2012     https://doi.org/10.3892/ijmm.2012.933
  • Pages: 989-998
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Abstract

The Na+-H+-exchanger-1 (NHE-1) controls intracellular pH and glycolytic enzyme activities, and its expression and activity are increased by diabetes and high glucose. NHE-1-dependent upregulation of the upper part of glycolysis, under conditions of inhibition (lens) or insufficient activation (retina) of glyceraldehyde 3-phosphate dehydrogenase, underlies diversion of the excessive glycolytic flux towards several pathways contributing to oxidative stress, a causative factor in diabetic cataractogenesis and retinopathy. This study evaluated the role for NHE-1 in diabetic cataract formation and retinal oxidative stress and apoptosis. Control and streptozotocin-diabetic rats were maintained with or without treatment with the NHE-1 inhibitor cariporide (Sanofi-Aventis, 10 mgkg-1d-1) for 3.5 months. In in vitro studies, bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without 10 µM cariporide, for 7 days. A several-fold increase of the by-product of glycolysis, α-glycerophosphate, indicative of activation of the upper part of glycolysis, was present in both rat lens and retina at an early (1-month) stage of streptozotocin-diabetes. Cariporide did not affect diabetic hyperglycemia and counteracted lens oxidative-nitrative stress and p38 MAPK activation, without affecting glucose or sorbitol pathway intermediate accumulation. Cataract formation (indirect ophthalmoscopy and slit-lamp examination) was delayed, but not prevented. The number of TUNEL-positive cells per flat-mounted retina was increased 4.4-fold in diabetic rats (101±17 vs. 23±8 in controls , P<0.01), and this increase was attenuated by cariporide (45±12, P<0.01). Nitrotyrosine and poly(ADP-ribose) fluorescence and percentage of TUNEL-positive cells were increased in pericytes and endothelial cells cultured in 30 mM glucose, and these changes were at least partially prevented by cariporide. In conclusion, NHE-1 contributes to diabetic cataract formation, and retinal oxidative-nitrative stress and apoptosis. The findings identify a new therapeutic target for diabetic ocular complications.

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June 2012
Volume 29 Issue 6

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

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Spandidos Publications style
Lupachyk S, Stavniichuk R, Komissarenko JI, Drel VR, Obrosov AA, El-Remessy AB, Pacher P and Obrosova IG: Na+/H+-exchanger-1 inhibition counteracts diabetic cataract formation and retinal oxidative-nitrative stress and apoptosis. Int J Mol Med 29: 989-998, 2012.
APA
Lupachyk, S., Stavniichuk, R., Komissarenko, J.I., Drel, V.R., Obrosov, A.A., El-Remessy , A.B. ... Obrosova, I.G. (2012). Na+/H+-exchanger-1 inhibition counteracts diabetic cataract formation and retinal oxidative-nitrative stress and apoptosis. International Journal of Molecular Medicine, 29, 989-998. https://doi.org/10.3892/ijmm.2012.933
MLA
Lupachyk, S., Stavniichuk, R., Komissarenko, J. I., Drel, V. R., Obrosov, A. A., El-Remessy , A. B., Pacher, P., Obrosova, I. G."Na+/H+-exchanger-1 inhibition counteracts diabetic cataract formation and retinal oxidative-nitrative stress and apoptosis". International Journal of Molecular Medicine 29.6 (2012): 989-998.
Chicago
Lupachyk, S., Stavniichuk, R., Komissarenko, J. I., Drel, V. R., Obrosov, A. A., El-Remessy , A. B., Pacher, P., Obrosova, I. G."Na+/H+-exchanger-1 inhibition counteracts diabetic cataract formation and retinal oxidative-nitrative stress and apoptosis". International Journal of Molecular Medicine 29, no. 6 (2012): 989-998. https://doi.org/10.3892/ijmm.2012.933