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Role of glyceraldehyde 3-phosphate dehydrogenase in the development and progression of diabetic retinopathy.

Kanwar M, Kowluru RA - Diabetes (2008)

Bottom Line: Reinstitution of good control failed to protect inactivation of GAPDH, its covalent modification, and translocation to the nucleus.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.

View Article: PubMed Central - PubMed

Affiliation: Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.

ABSTRACT

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.

Research design and 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.

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Related in: MedlinePlus

Histopathology in retinal microvasculature of normal rats (left panel) and those in a state of poor control (right panel). Trypsin-digested retinal microvasculature was stained with periodic acid Schiff and hematoxylin. The number of acellular capillaries was counted in multiple midretinal fields and standardized to retinal area (per square millimeter). The arrows indicate acellular capillaries in the trypsin-digested microvessels obtained from a rat that was maintained in poor control for 12 months. (Please see http://dx.doi.org/10.2337/db08-1025 for a high-quality digital representation of this figure.)
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f7: Histopathology in retinal microvasculature of normal rats (left panel) and those in a state of poor control (right panel). Trypsin-digested retinal microvasculature was stained with periodic acid Schiff and hematoxylin. The number of acellular capillaries was counted in multiple midretinal fields and standardized to retinal area (per square millimeter). The arrows indicate acellular capillaries in the trypsin-digested microvessels obtained from a rat that was maintained in poor control for 12 months. (Please see http://dx.doi.org/10.2337/db08-1025 for a high-quality digital representation of this figure.)

Mentions: Poor glycemic control in rats for 12 months increased the number of acellular capillaries in the retinal vasculature (Fig. 7) by about fourfold compared with that in normal rats. The 6 months of good control that followed 6 months of poor control failed to provide any protection; the number of acellular capillaries was similar in poor-control and poor control–good control rats (average number of acellular capillaries per millimeter squared of retina in rats in the normal, poor-control, and poor control–good control groups: 1.5, 6.1, and 6.8, respectively).


Role of glyceraldehyde 3-phosphate dehydrogenase in the development and progression of diabetic retinopathy.

Kanwar M, Kowluru RA - Diabetes (2008)

Histopathology in retinal microvasculature of normal rats (left panel) and those in a state of poor control (right panel). Trypsin-digested retinal microvasculature was stained with periodic acid Schiff and hematoxylin. The number of acellular capillaries was counted in multiple midretinal fields and standardized to retinal area (per square millimeter). The arrows indicate acellular capillaries in the trypsin-digested microvessels obtained from a rat that was maintained in poor control for 12 months. (Please see http://dx.doi.org/10.2337/db08-1025 for a high-quality digital representation of this figure.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2606877&req=5

f7: Histopathology in retinal microvasculature of normal rats (left panel) and those in a state of poor control (right panel). Trypsin-digested retinal microvasculature was stained with periodic acid Schiff and hematoxylin. The number of acellular capillaries was counted in multiple midretinal fields and standardized to retinal area (per square millimeter). The arrows indicate acellular capillaries in the trypsin-digested microvessels obtained from a rat that was maintained in poor control for 12 months. (Please see http://dx.doi.org/10.2337/db08-1025 for a high-quality digital representation of this figure.)
Mentions: Poor glycemic control in rats for 12 months increased the number of acellular capillaries in the retinal vasculature (Fig. 7) by about fourfold compared with that in normal rats. The 6 months of good control that followed 6 months of poor control failed to provide any protection; the number of acellular capillaries was similar in poor-control and poor control–good control rats (average number of acellular capillaries per millimeter squared of retina in rats in the normal, poor-control, and poor control–good control groups: 1.5, 6.1, and 6.8, respectively).

Bottom Line: Reinstitution of good control failed to protect inactivation of GAPDH, its covalent modification, and translocation to the nucleus.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.

View Article: PubMed Central - PubMed

Affiliation: Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.

ABSTRACT

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.

Research design and 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.

Show MeSH
Related in: MedlinePlus