Early diabetes-induced biochemical changes in the retina: comparison of rat and mouse models
Open accessAbstract
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, alpha-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 approximately 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.
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In retinal mitochondria from STZ diabetic rats, NAD+/NADH ratio is reduced, consistent with hypoxia.
“Another study of retinal mitochondria from STZ diabetic rats reported a reduction in the NAD+/NADH ratio, consistent with hypoxia (242).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [242]
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- Authors
- Obrosova, I. G., Drel, V. R., Kumagai, A. K., Szábo, C., Pacher, P., & Stevens, M. J.
- Affiliations
- Pennington Biomedical Research Center (US)
- University of Michigan (US)
- National Institutes of Health (US)
- Corresponding author
- Obrosova, I. G.
- Venue
- Diabetologia
- Published
- 2006-08-01
- Volume
- 49
- Issue
- 10
- Pages
- 2525-2533
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC2228251
- OpenAlex
- W2123307497
- Cited by
- 92
- References
- 45
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 6 · 2015: 7 · 2014: 3 · 2013: 7 · 2012: 4
- FWCI
- 5.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (Z01AA000375)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- diabetic retinopathy, streptozotocin-induced diabetes, fructose accumulation, oxidative stress, antioxidant enzymes, superoxide dismutase, glutathione peroxidase, poly(ADP-ribosyl)ation, VEGF overexpression, NAD+/NADH ratio, retinal hypoxia, lipid peroxidation, malondialdehyde, animal model selection, lactate
- MeSH terms
- Animals, Blood Glucose, Catalase, Diabetes Mellitus, Experimental, Diabetic Retinopathy, Enzyme-Linked Immunosorbent Assay, Male, Mice, Inbred C57BL, Reference Values, Retina, Species Specificity, Rats, Wistar, Glutathione Disulfide, Vascular Endothelial Growth Factor A, Mice, Rats
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