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I.G. Obrosova, G.M. Seigel, R.N. Frank, O.I. Abatan, P. Pacher, K. Komjati, M.J. Stevens, C. Szabo; Early Diabetes-Induced Changes in the Retina: Comparison of STZ Models in Rat and Mouse . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4521.
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Purpose: Various transgenic and knockout models are now available for studying the pathogenesis of diabetic retinopathy (DR). Diabetes-induced changes in the wild-type mice are poorly explored. We compared early retinal changes in STZ-induced rat and mouse models. Methods: The experiments were performed on control (C) and diabetic(D) male Wistar rats and male C57Bl/6J mice. The duration of STZ-diabetes was 6 weeks. Concentrations of glucose, sorbitol, fructose, lactate, pyruvate, glutamate, α-ketoglutarate and ammonia were assayed spectrofluorometrically by enzymatic procedures, VEGF protein by ELISA and poly(ADP-ribose) and TUNEL immunoreactivities by immunocytochemistry. Free mitochondrial and cytosolic NAD+/NADH ratios were calculated from the glutamate and lactate dehydrogenase systems. Results: Blood glucose concentrations were in the range of 350-420 mg/dl in both D rats and mice. Retinal glucose concentrations were increased 6- and 5-fold in D rats and mice, respectively, vs C. D rats manifested ~10-fold and 6-fold accumulation of retinal sorbitol and fructose whereas accumulation of sorbitol (Mean±SD, 1.80±0.74 vs 1.19±0.60 nmol/mg prot in C) and fructose (13.6±3.0 vs 7.4±1.1 nmol/mg prot in C, p<0.05) in D mice was quite modest. Correspondingly, D rats had increased retinal malondialdehyde plus 4-hydroxyalkenal concentrations, reduced superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione transferase activities and increased poly(ADP-ribose) immunoreactivity whereas mice had no manifestations of retinal oxidative stress or poly(ADP-ribosyl)ation. D, but not C, rats had 1-3 TUNEL positive cells in the neural retina per 4 micron thick ocular section whereas all D mouse samples were negative. D rats had decreased free mitochondrial and cytosolic NAD+/NADH ratios, consistent with retinal hypoxia, whereas D mice preserved both ratios in the normal range.VEGF concentrations were increased 2-fold in D rats, and were normal in D mice. Conclusions: Our findings are consistent with the absence of retinal vascular and neural abnormalities in D mice in several other reports. Development of transgenic and knockout mice with clearly manifest sorbitol pathway hyperactivity, enhanced oxidative stress/apoptosis, poly(ADP-ribosyl)ation or redox changes can dissect the role of each of these factors in the pathogenesis of DR.
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