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Irina G. Obrosova, Yury Maksimchyk, Roman Stavniichuk, Sergey Lupachyk, Ulrich Julius, Viktor R. Drel; The Na+/H+-Exchanger-1 Inhibitor Cariporide Delays Diabetic Cataract Formation through Alleviation of Oxidative Stress. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2086.
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Na+-H+-exchanger-1 (NHE-1) controls intracellular pH and glycolytic enzyme activities, and its expression and activity are increased by diabetes. Diabetes-induced upregulation of the upper part of glycolysis under conditions of inhibition of glyceraldehyde 3-phosphate dehydrogenase underlies diversion of the excessive glycolytic flux towards several pathways leading to oxidative stress, a factor contributing to cataract formation. We evaluated the role for NHE-1 in lens oxidative-nitrosative stress, sorbitol pathway activation, MAPK signaling, and cataractogenesis associated with diabetes.
Mature (body weigt 300-350 g) control (C) and STZ-diabetic (D) rats were maintained with or without the NHE-1 inhibitor cariporide (CP, Sanofi-Aventis, 10 mgkg-1d-1) treatment for 3.5 mo. Diabetic rats received suboptimal doses of insulin to prevent ketoacidosis and weight loss. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination weekly. Cataracts were scored (0 - clear lenses, 1-vacuoles, 2-opacities, 3-mature cataract). A part of the rats were killed after 4 wks of D, and lenses were collected for measurements of 4-hydroxynonenal (HNE) adducts and nitrotyrosine (NT) by ELISA, sorbitol pathway intermediates by enzymatic assays, and total and phosphorylated p38 MAPK and ERK by Western blot analysis. The data are expressed as Mean± SEM.
All the lenses were clear 2 wks after induction of D. During the next three wks, CP delayed diabetic cataract formation (0.133± 0.091 vs 0.667 ± 0.130; 0.267 ± 0.118 vs 0.867 ± 0.115; and 0.333 ± 0.126 vs 0.967 ± 0.102 in untreated D, p < 0.01 for all comparisons). This trend maintained during the next three wks, but the cataract scores did not differ significantly from those in untreated D. Lenses of rats with 4-wk D displayed a dramatic sorbitol pathway intermediate accumulation, oxidative-nitrosative stress, and p38 MAPK, but not ERK, activation. CP prevented diabetes-induced increase in HNE adduct (2.15 ± 0.17 vs 3.0 ± 0.21 pmol/mg prot in untreated D, p < 0.01, and vs 1.94 ± 0.16 in C) and NT (2.61 ± 0.53 vs 4.17 ± 0.57 pmol/mg prot in untreated D, and vs 2.72 ± 0.24 in C) levels, and phospho-p38 MAPK/total p38 MAPK ratio, without affecting sorbitol pathway intermediate accumulation.
NHE-1 contributes to diabetic cataract formation through oxidative-nitrosative stress, and, potentially, p38 MAPK activation, and independent of sorbitol pathway activity.
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