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

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.

• Authors: Sergey Lupachyk, Roman Stavniichuk, Julia I Komissarenko, Viktor R Drel, Alexander A Obrosov, Azza B El-Remessy, Pal Pacher, Irina G Obrosova
• Journal: International journal of molecular medicine (Int J Mol Med) Vol. 29 Issue 6 Pg. 989-98 (Jun 2012) ISSN: 1791-244X [Electronic] Greece
• PMID: 22407349 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Aldehydes
• Blood Glucose
• Guanidines
• Sodium-Hydrogen Exchangers
• Sulfones
• 3-nitrotyrosine
• Tyrosine
• cariporide
• Poly(ADP-ribose) Polymerases
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• 4-hydroxy-2-nonenal

Topics

• Aldehydes (metabolism)
• Animals
• Apoptosis (drug effects)
• Blood Glucose (metabolism)
• Blotting, Western
• Cataract (blood, drug therapy, pathology)
• Cattle
• Diabetes Complications (blood, drug therapy, pathology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fasting (blood)
• Guanidines (pharmacology, therapeutic use)
• In Situ Nick-End Labeling
• Lens, Crystalline (drug effects, enzymology, pathology)
• Male
• Nitrosation (drug effects)
• Oxidative Stress (drug effects)
• Phosphorylation (drug effects)
• Poly(ADP-ribose) Polymerases (metabolism)
• Rats
• Rats, Wistar
• Retina (pathology)
• Sodium-Hydrogen Exchangers (antagonists & inhibitors, metabolism)
• Sulfones (pharmacology, therapeutic use)
• Tyrosine (analogs & derivatives, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)