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

• Published in: Diabetologia Vol. 49; no. 10; pp. 2525 - 2533
• Main Authors: Obrosova, I. G, Drel, V. R, Kumagai, A. K, Szábo, C, Pacher, P, Stevens, M. J
• Format: Journal Article
• Language: English
• Published: Berlin Berlin/Heidelberg : Springer-Verlag 01.10.2006; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Biomedical research; Blood Glucose - metabolism; Catalase - metabolism; Diabetes; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic Retinopathy - physiopathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Enzymes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; Glucose; Glutathione Disulfide - metabolism; Kinases; Laboratories; Male; Medical sciences; Mice; Mice, Inbred C57BL; NAD⁺/NADH ratio; oxidative stress; Poly(ADP-ribosyl)ation; Proteins; Ratios; Rats; Rats, Wistar; Reference Values; Retina; Retina - physiopathology; Sorbitol pathway of glucose metabolism; Species Specificity; Streptozotocin diabetes; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - analysis; Vertebrates: nervous system and sense organs; United States > US; Endocrinopathy; Sorbitol; Animal model; Oxidative stress; Streptozotocin diabetes; Rat; Retina; Glucose; ADP; Eye; Visual system; NADH; Streptozotocin; Mouse NAD+/NADH ratio; Vascular endothelial growth factor; Diabetes mellitus; Rodentia; Metabolism; Sorbitol pathway of glucose metabolism; Vertebrata; Mammalia; Vascular endothelium growth factor; Mouse; Animal; Poly(ADP-ribosyl)ation
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0356-7

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.