Na+/H+‐exchanger‐1 inhibition delays diabetic cataract formation and prevents retinal apoptosis and oxidative stress

Abstract

Na+‐H+‐exchanger‐1 (NHE‐1) controls intracellular pH and glycolytic enzyme activities, and its expression and activity are increased by diabetes. We evaluated the role for NHE‐1 in diabetic cataract formation and retinal oxidative‐nitrosative stress and apoptosis. Control and STZ‐diabetic rats were treated with/without the NHE‐1 inhibitor cariporide (C, Sanofi‐Aventis, 10 mgkg−1d−1) for 1(lens biochemistry) and 3.5 mo. 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 d. C treatment delayed, but did not prevent, diabetic cataractogenesis. This was probably related to inhibition of oxidative‐nitrosative stress in the lens. Diabetes‐induced accumulation of glucose and sorbitol pathway metabolites was not affected. The number of TUNEL positive cells was increased 4.4‐fold in the retina of diabetic rats, and this increase was attenuated, but not completely prevented, by C. Nitrotyrosine fluorescence and TUNEL positivity were increased in pericytes and endothelial cells cultured in 30 mM glucose, and both nitrosative stress and cell death were at least partially prevented by C. In conclusion, NHE‐1 contributes to diabetic cataract formation and retinal oxidative‐nitrosative stress and apoptosis. The findings identify a new therapeutic target for diabetic ocular complications.