TY - JOUR
T1 - Early diabetes-induced biochemical changes in the retina
T2 - Comparison of rat and mouse models
AU - Obrosova, I. G.
AU - Drel, V. R.
AU - Kumagai, A. K.
AU - Szábo, C.
AU - Pacher, P.
AU - Stevens, M. J.
N1 - Funding Information:
Acknowledgements This study was supported by the grants from the Juvenile Diabetes Research Foundation Center for the Study of Complications of Diabetes Grant 4-200-421 (I. G. Obrosova, A. K. Kumagai, M. J. Stevens) and the American Diabetes Association (I. G. Obrosova). The immunohistochemistry work was supported by the Intramural Research Program of the NIAAA/NIH (P. Pacher).
PY - 2006/10
Y1 - 2006/10
N2 - Aims/hypothesis: Recently, various transgenic and knock-out mouse models have become available for studying the pathogenesis of diabetic retinopathy. At the same time, diabetes-induced retinal changes in the wild-type mice remain poorly characterised. The present study compared retinal biochemical changes in rats and mice with similar (6-week) durations of streptozotocin-induced diabetes. Materials and methods: The experiments were performed on Wistar rats and C57Bl6/J mice. Retinal glucose, sorbitol, fructose, lactate, pyruvate, glutamate, α-ketoglutarate and ammonia were measured spectrofluorometrically by enzymatic methods. Vascular endothelial growth factor (VEGF) protein was assessed by ELISA, and poly(ADP-ribosyl)ation by immunohistochemistry and western blot analysis. Free mitochondrial and cytosolic NAD+/NADH ratios were calculated from the glutamate and lactate dehydrogenase systems. Results: Retinal glucose concentrations were similarly increased in diabetic rats and mice, vs controls. Diabetic rats manifested ∼26- and 5-fold accumulation of retinal sorbitol and fructose, respectively, whereas elevation of both metabolites in diabetic mice was quite modest. Correspondingly, diabetic rats had (1) increased retinal malondialdehyde plus 4-hydroxyalkenal concentrations, (2) reduced superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase and glutathione transferase activities, (3) slightly increased poly(ADP-ribose) immunoreactivity and poly(ADP-ribosyl)ated protein abundance, and (4) VEGF protein overexpression. Diabetic mice lacked these changes. SOD activity was 21-fold higher in murine than in rat retinas (the difference increased to 54-fold under diabetic conditions), whereas other antioxidative enzyme activities were 3- to 10-fold lower. With the exception of catalase, the key antioxidant defence enzyme activities were increased, rather than reduced, in diabetic mice. Diabetic rats had decreased free mitochondrial and cytosolic NAD+/NADH ratios, consistent with retinal hypoxia, whereas both ratios remained in the normal range in diabetic mice. Conclusions/interpretation: Mice with short-term streptozotocin-induced diabetes lack many biochemical changes that are clearly manifest in the retina of streptozotocin-diabetic rats. This should be considered when selecting animal models for studying early retinal pathology associated with diabetes.
AB - Aims/hypothesis: Recently, various transgenic and knock-out mouse models have become available for studying the pathogenesis of diabetic retinopathy. At the same time, diabetes-induced retinal changes in the wild-type mice remain poorly characterised. The present study compared retinal biochemical changes in rats and mice with similar (6-week) durations of streptozotocin-induced diabetes. Materials and methods: The experiments were performed on Wistar rats and C57Bl6/J mice. Retinal glucose, sorbitol, fructose, lactate, pyruvate, glutamate, α-ketoglutarate and ammonia were measured spectrofluorometrically by enzymatic methods. Vascular endothelial growth factor (VEGF) protein was assessed by ELISA, and poly(ADP-ribosyl)ation by immunohistochemistry and western blot analysis. Free mitochondrial and cytosolic NAD+/NADH ratios were calculated from the glutamate and lactate dehydrogenase systems. Results: Retinal glucose concentrations were similarly increased in diabetic rats and mice, vs controls. Diabetic rats manifested ∼26- and 5-fold accumulation of retinal sorbitol and fructose, respectively, whereas elevation of both metabolites in diabetic mice was quite modest. Correspondingly, diabetic rats had (1) increased retinal malondialdehyde plus 4-hydroxyalkenal concentrations, (2) reduced superoxide dismutase (SOD), glutathione peroxidase, glutathione reductase and glutathione transferase activities, (3) slightly increased poly(ADP-ribose) immunoreactivity and poly(ADP-ribosyl)ated protein abundance, and (4) VEGF protein overexpression. Diabetic mice lacked these changes. SOD activity was 21-fold higher in murine than in rat retinas (the difference increased to 54-fold under diabetic conditions), whereas other antioxidative enzyme activities were 3- to 10-fold lower. With the exception of catalase, the key antioxidant defence enzyme activities were increased, rather than reduced, in diabetic mice. Diabetic rats had decreased free mitochondrial and cytosolic NAD+/NADH ratios, consistent with retinal hypoxia, whereas both ratios remained in the normal range in diabetic mice. Conclusions/interpretation: Mice with short-term streptozotocin-induced diabetes lack many biochemical changes that are clearly manifest in the retina of streptozotocin-diabetic rats. This should be considered when selecting animal models for studying early retinal pathology associated with diabetes.
KW - Mouse
KW - NAD/NADH ratio
KW - Oxidative stress
KW - Poly(ADP-ribosyl)ation
KW - Rat
KW - Retina
KW - Sorbitol pathway of glucose metabolism
KW - Streptozotocin diabetes
KW - Vascular endothelial growth factor
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U2 - 10.1007/s00125-006-0356-7
DO - 10.1007/s00125-006-0356-7
M3 - Article
C2 - 16896942
AN - SCOPUS:33748516742
SN - 0012-186X
VL - 49
SP - 2525
EP - 2533
JO - Diabetologia
JF - Diabetologia
IS - 10
ER -