Role of glyceraldehyde 3-phosphate dehydrogenase in the development and progression of diabetic retinopathy.
OBJECTIVE
Mitochondrial superoxide levels are elevated in the retina in diabetes, and manganese superoxide dismutase overexpression prevents the development of retinopathy. Superoxide inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which activates major pathways implicated in diabetic complications, including advanced glycation end products (AGEs), protein kinase C, and hexosamine pathway. Our aim is to investigate the role of GAPDH in the development and progression of diabetic retinopathy and to elucidate the mechanism.


METHODS
Rats with streptozotocin-induced diabetes were in a state of poor control (GHb >11%) for 12 months, good control (GHb <7) soon after induction of diabetes, or poor control for 6 months with 6 months' good control. Retinal GAPDH, its ribosylation and nitration, AGEs, and PKC activation were determined and correlated with microvascular histopathology.


RESULTS
In rats with poor control, retinal GAPDH activity and expressions were subnormal with increased ribosylation and nitration (25-30%). GAPDH activity was subnormal in both cytosol and nuclear fractions, but its protein expression and nitration were significantly elevated in nuclear fraction. Reinstitution of good control failed to protect inactivation of GAPDH, its covalent modification, and translocation to the nucleus. PKC, AGEs, and hexosamine pathways remained activated, and microvascular histopathology was unchanged. However, GAPDH and its translocation in good control rats were similar to those in normal rats.


CONCLUSIONS
GAPDH plays a significant role in the development of diabetic retinopathy and its progression after cessation of hyperglycemia. Thus, therapies targeted toward preventing its inhibition may inhibit development of diabetic retinopathy and arrest its progression.
Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.
Mamta
M
Kanwar
Renu A
RA
Kowluru
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D018450:Disease Progression; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011499:Protein Processing, Post-Translational; D051381:Rats; D012160:Retina / Q000378:metabolism / Q000473:pathology
D005987:Glyceraldehyde-3-Phosphate Dehydrogenases