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1From the Departments of Physiology and Biophysics, 3Medicine, and 4Ophthalmology and the 5Center for Diabetes Research, Case Western Reserve University, Cleveland, Ohio; and the 2Department of Ophthalmology, Northwestern University, Chicago, Illinois.
PURPOSE. A recent study demonstrated that retinal Müller cells undergo hyperglycemia-induced apoptosis in vitro. Translocation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the cytosol to the nucleus is a critical step in the induction of apoptosis in neuronal cells. R-(–)-deprenyl prevents nuclear translocation of GAPDH and subsequent apoptosis in neuronal cells. In this study, the role of nuclear translocation of GAPDH in hyperglycemia-induced apoptosis in retinal Müller cells and the ability of R-(–)-deprenyl to inhibit the translocation of GAPDH and apoptosis were investigated.
METHODS. Transformed rat Müller cells (rMC-1) and isolated human Müller cells were cultured in normal glucose, high glucose, and high glucose plus R-(–)-deprenyl for up to 5 days. Subcellular distribution of GAPDH was determined in vitro and in vivo by immunocytochemistry. Apoptosis in tissue cultures was determined by annexin-V staining and caspase-3 activity.
RESULTS. Hyperglycemia significantly increased the amount of GAPDH protein in the nucleus above normal within the first 48 hours in rMC-1 and human Müller cells. The addition of R-(–)-deprenyl to these cells incubated in high glucose reduced the amount of GAPDH protein in the nucleus and decreased hyperglycemia-induced apoptosis in both cell types. In vivo studies confirmed the accumulation of GAPDH in nuclei of Müller cells in diabetes.
CONCLUSIONS. The nuclear translocation of GAPDH in rMC-1 and human Müller cells is closely associated with the induction of apoptosis. R-(–)-deprenyl inhibits nuclear accumulation of GAPDH and subsequent apoptosis in these cells. Therefore, R-(–)-deprenyl offers a strategy to explore the role of GAPDH translocation into the nucleus in the development of diabetic retinopathy.
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