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I. G. Obrosova, V. R. Drel, J. Shin, B. A. Pillai, U. A. Julius, A. B. El-Remessy; Na+/H+- Exchanger-1 Inhibition Counteracts Diabetes-Induced Cataractogenesis and Retinal Oxidative Stress and Apoptosis. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5358.
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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 and high glucose. Upregulation of the upper part of glycolysis under conditions of inhibition (lens) or insufficient activation (retina) of glyceraldehyde 3-phosphate dehydrogenase underlies diversion of excessive glycolytic flux towards several pathways contributing to oxidative stress, a causative factor in diabetic cataractogenesis and retinopathy. We evaluated the role for NHE-1 in diabetic cataract formation and retinal oxidative stress and apoptosis.
Mature control and STZ-diabetic rats were treated with/without the NHE-1 inhibitor cariporide (C, Sanofi-Aventis, 10 mgkg-1d-1) for 3.5 mo. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination on a weekly basis. A by-product of glycolysis, -glycerophosphate (GP), was measured in the lens and retina by enzymatic spectrofluorometric assay. Cell death was assessed in flat-mounted retinas by TUNEL immunoperoxidase staining. In in vitro studies, bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without 10 µM C, for 7 days. Nitrotyrosine (NT), poly(ADP-ribose), and TUNEL-positivity were assessed by fluorescent immunocytochemistry.
A several-fold increase of GP, indicative of activation of the upper part of glycolysis, was present in both rat lens and retina at early (1-1.5 mo) stage of STZ-diabetes. C treatment delayed, but did not prevent, diabetic cataractogenesis. The number of TUNEL positive cells was increased 4.4-fold in diabetic rats compared with controls (101 ± 17 vs 23 ± 8 per retina, p < 0.01), and this increase was attenuated, but not completely prevented, by C (45 ± 12, p < 0.01 vs untreated diabetic group). Nitrotyrosine and poly(ADP-ribose) fluorescence and percentage of TUNEL-positive cells were increased in pericytes and endothelial cells cultured in 30 mM glucose, vs those cultured in 5 mM glucose. Nitrosative stress, poly(ADP-ribose) accumulation, and cell death were completely or partially prevented by C.
NHE-1 contributes to diabetic cataract formation, retinal oxidative-nitrosative stress, PARP activation, and premature cell death. The findings identify new therapeutic target and provide rationale for detailed evaluation of NHE-1 inhibitors on diabetic ocular complications.
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