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

Lupachyk S, Stavniichuk R, Komissarenko JI, Drel VR, Obrosov AA, El-Remessy AB, Pacher P, Obrosova IG - Int. J. Mol. Med. (2012)

Bottom Line: Cariporide did not affect diabetic hyperglycemia and counteracted lens oxidative-nitrative stress and p38 MAPK activation, without affecting glucose or sorbitol pathway intermediate accumulation.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.

View Article: PubMed Central - PubMed

Affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.

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.

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Lens 4-hydroxynonenal adducts and nitrotyrosine concentrations in control and diabetic rats maintained with or without cariporide treatment. C, control group; D, diabetic group; Ca, cariporide; 4-HNE, 4-hydroxynonenal. Mean ± SEM, n=6/group. *P<0.05 and **P<0.01 vs. the controls; #P<0.05 and ##P<0.01 vs. the untreated diabetic group.
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f3-ijmm-29-06-0989: Lens 4-hydroxynonenal adducts and nitrotyrosine concentrations in control and diabetic rats maintained with or without cariporide treatment. C, control group; D, diabetic group; Ca, cariporide; 4-HNE, 4-hydroxynonenal. Mean ± SEM, n=6/group. *P<0.05 and **P<0.01 vs. the controls; #P<0.05 and ##P<0.01 vs. the untreated diabetic group.

Mentions: Lens HNE adducts and NT concentrations were increased by 55 and 53%, respectively, in rats with 1-month duration of diabetes, compared with the non-diabetic controls (Fig. 3). Diabetes-induced HNE adduct and NT accumulation was essentially prevented by cariporide treatment. Cariporide did not reduce either HNE adduct or NT concentrations in the non-diabetic rats.


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

Lupachyk S, Stavniichuk R, Komissarenko JI, Drel VR, Obrosov AA, El-Remessy AB, Pacher P, Obrosova IG - Int. J. Mol. Med. (2012)

Lens 4-hydroxynonenal adducts and nitrotyrosine concentrations in control and diabetic rats maintained with or without cariporide treatment. C, control group; D, diabetic group; Ca, cariporide; 4-HNE, 4-hydroxynonenal. Mean ± SEM, n=6/group. *P<0.05 and **P<0.01 vs. the controls; #P<0.05 and ##P<0.01 vs. the untreated diabetic group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3375174&req=5

f3-ijmm-29-06-0989: Lens 4-hydroxynonenal adducts and nitrotyrosine concentrations in control and diabetic rats maintained with or without cariporide treatment. C, control group; D, diabetic group; Ca, cariporide; 4-HNE, 4-hydroxynonenal. Mean ± SEM, n=6/group. *P<0.05 and **P<0.01 vs. the controls; #P<0.05 and ##P<0.01 vs. the untreated diabetic group.
Mentions: Lens HNE adducts and NT concentrations were increased by 55 and 53%, respectively, in rats with 1-month duration of diabetes, compared with the non-diabetic controls (Fig. 3). Diabetes-induced HNE adduct and NT accumulation was essentially prevented by cariporide treatment. Cariporide did not reduce either HNE adduct or NT concentrations in the non-diabetic rats.

Bottom Line: Cariporide did not affect diabetic hyperglycemia and counteracted lens oxidative-nitrative stress and p38 MAPK activation, without affecting glucose or sorbitol pathway intermediate accumulation.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.

View Article: PubMed Central - PubMed

Affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.

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.

Show MeSH
Related in: MedlinePlus