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

作者：Lupachyk Sergey; Stavniichuk Roman; Komissarenko Julia I; Drel Viktor R; Obrosov Alexander A; El Remessy Azza B; Pacher Pal; Obrosova Irina G^*

来源：International Journal of Molecular Medicine, 2012, 29(6): 989-998.

DOI：10.3892/ijmm.2012.933

• apoptosis
• cariporide
• diabetic cataract
• early diabetic retinopathy
• retinal endothelial cell
• Na+/H+-exchanger-1
• oxidative-nitrative stress
• retinal pericyte

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 mg.kg(-1)d(-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 mu M cariporide, for 7 days. A several-fold increase of the by-product of glycolysis, alpha-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%26lt;0.01), and this increase was attenuated by cariporide (45 +/- 12, P%26lt;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.

• 出版日期2012-6