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(Investigative Ophthalmology and Visual Science. 2004;45:1553-1561.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-1294
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Nuclear Translocation of Glyceraldehyde-3-Phosphate Dehydrogenase: A Role in High Glucose-Induced Apoptosis in Retinal Müller Cells

Linda L. Kusner,1 Vijay P. Sarthy,2 and Susanne Mohr1,3,4,5

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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