Early diabetes-induced biochemical changes in the retina: Comparison of rat and mouse models

I. G. Obrosova, V. R. Drel, A. K. Kumagai, C. Szábo, P. Pacher, M. J. Stevens

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    69 Scopus citations

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)2525-2533
    Number of pages9
    JournalDiabetologia
    Volume49
    Issue number10
    DOIs
    StatePublished - Oct 1 2006

    Keywords

    • Mouse
    • NAD/NADH ratio
    • Oxidative stress
    • Poly(ADP-ribosyl)ation
    • Rat
    • Retina
    • Sorbitol pathway of glucose metabolism
    • Streptozotocin diabetes
    • Vascular endothelial growth factor

    ASJC Scopus subject areas

    • Internal Medicine
    • Endocrinology, Diabetes and Metabolism

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    Obrosova, I. G., Drel, V. R., Kumagai, A. K., Szábo, C., Pacher, P., & Stevens, M. J. (2006). Early diabetes-induced biochemical changes in the retina: Comparison of rat and mouse models. Diabetologia, 49(10), 2525-2533. https://doi.org/10.1007/s00125-006-0356-7