Role of Glyceraldehyde 3-Phosphate Dehydrogenase in the Development and Progression of Diabetic Retinopathy

Abstract

Objective: Mitochondrial superoxide levels are elevated in the retina in diabetes, and MnSOD overexpression prevents the development of retinopathy. Superoxide inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which activates major pathways implicated in diabetic complications, including 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.

Research Design: Streptozotocin diabetic rats were either in poor control (PC, glycated hemoglobin>11%) for 12 months, or good control (GC, GHb<7) soon after induction of diabetes, or six months PC with six months GC (PC-GC). Retinal GAPDH, its ribosylation and nitration and AGEs and PKC activation were determined, and correlated with microvascular histopathology.

Results: In PC rats 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. Re-institution 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 unchanged. However, GAPDH and its translocation in GC 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 towards preventing its inhibition may inhibit development of diabetic retinopathy and arrest its progression.