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

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

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 streptozotocindiabetic 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 streptozotocindiabetes. 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 flatmounted 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(ADPribose) 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.

Original languageEnglish (US)
Pages (from-to)989-998
Number of pages10
JournalInternational journal of molecular medicine
Volume29
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

Keywords

  • Apoptosis
  • Cariporide
  • Diabetic cataract
  • Early diabetic retinopathy
  • Na /H -exchanger-1
  • Oxidative-nitrative stress
  • Retinal endothelial cell
  • Retinal pericyte

ASJC Scopus subject areas

  • Genetics

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