RGD Reference Report - Na+/H+-exchanger-1 inhibition counteracts diabetic cataract formation and retinal oxidative-nitrative stress and apoptosis. - Rat Genome Database

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

Authors: Lupachyk, S  Stavniichuk, R  Komissarenko, JI  Drel, VR  Obrosov, AA  El-Remessy, AB  Pacher, P  Obrosova, IG 
Citation: Lupachyk S, etal., Int J Mol Med. 2012 Jun;29(6):989-98. doi: 10.3892/ijmm.2012.933. Epub 2012 Mar 7.
RGD ID: 8693684
Pubmed: PMID:22407349   (View Abstract at PubMed)
PMCID: PMC3375174   (View Article at PubMed Central)
DOI: DOI:10.3892/ijmm.2012.933   (Journal Full-text)

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 microM 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<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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cataract  ISOSlc9a1 (Rattus norvegicus)8693684; 8693684associated with Diabetes Mellitus and ExperimentalRGD 
cataract  IMP 8693684associated with Diabetes Mellitus and ExperimentalRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of apoptotic process  IMP 8693684 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc9a1  (solute carrier family 9 member A1)

Genes (Mus musculus)
Slc9a1  (solute carrier family 9 (sodium/hydrogen exchanger), member 1)

Genes (Homo sapiens)
SLC9A1  (solute carrier family 9 member A1)


Additional Information