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L.L. Kusner, S. Mohr; Nuclear Translocation of Glyceraldehyde-3-Phosphate Dehydrogenase, a Role in High Glucose-Induced Apoptosis of Retinal Müller Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3874.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Several studies have shown that cells of the retina and its microvasculature die at an accelerated rate in diabetic retinopathy. We have recently demonstrated that Müller cells undergo hyperglycemia- induced apoptosis in vitro. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis, has been recently associated with the induction of apoptosis in neuronal cells by translocation of the protein to the nucleus. R-(-)-deprenyl, a monoamine oxidase-B inhibitor, has been found to prevent nuclear translocation of GAPDH in neuronal cells and subsequent apoptosis. This study focused on hyperglycemia-induced GAPDH nuclear translocation and the effect of R-(-)-deprenyl on the high glucose-induced translocation and apoptosis in Müller cells. Methods: Transformed rat Müller cells (rMC-1) were cultured in low glucose (5mM), high glucose (25mM) and high glucose plus R-(-)-deprenyl (1nM) for up to 5 days. Subcellular distribution of GAPDH was determined by western blots of fractioned cell lysates and immunohistochemistry of cultured rMC-1 cells using an antibody to GAPDH. Apoptotic events were determined by annexin-V staining, bax expression and measurement of caspase activities. Results: GAPDH translocated to the nucleus from the cytosol within the first 48 hours of high glucose treatment of rMC-1 cells, whereas, GAPDH remained cytosolic in low glucose environment. The addition of R-(-)-deprenyl reduced the level of high glucose induced nuclear GAPDH as observed in both western blots and immunohistochemistry. In addition, R-(-)-deprenyl reduced the activation of caspases, bax expression and apoptosis in rMC-1 cells. Conclusions: Hyperglycemia results in the nuclear translocation of GAPDH and apoptosis in Müller cells. All of these glucose-induced abnormalities were inhibited by R-(-)-deprenyl. R-(-)-deprenyl might represent a new therapeutic strategy in the prevention of diabetic retinopathy.
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