Validation of structural and functional lesions of diabetic retinopathy in mice

Department of Medicine, Case Western Reserve University, Veterans Affairs Medical Center, Cleveland, OH 44106-4951, USA.
Molecular vision (Impact Factor: 1.99). 10/2010; 16:2121-31.
Source: PubMed


Diabetic retinopathy is a serious long-term complication of diabetes mellitus. There is considerable interest in using mouse models, which can be genetically modified, to understand how retinopathy develops and can be inhibited. Not all retinal lesions that develop in diabetic patients have been reproduced in diabetic mice; conversely, not all abnormalities found in diabetic mice have been studied or identified in diabetic patients. Thus, it is important to recognize which structural and functional abnormalities that develop in diabetic mice have been validated against the lesions that characteristically develop in diabetic patients. Those lesions that have been observed to develop in the mouse models to date are predominantly characteristic of the early stages of retinopathy. Identification of new therapeutic ways to inhibit these early lesions is expected to help inhibit progression to more advanced and clinically important stages of retinopathy.

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    • "Supporting this finding, our lab finds no photoregulation of 1/T1r in the inner retina in (i) guinea pigs (which are without an inner retinal circulation , data not shown) and (ii) diabetic mice (Fig. 4). The data in the diabetic mice are particularly relevant because diabetes is known to impair retinal vascular autoregulation (Kern et al., 2010). Since the retinal circulation provides ~10% of the oxygen required by the photoreceptors in the dark to support the great energy needed for continuous ion channel opening (41e44), evaluating the photoregulatory changes in inner retina blood volume is likely useful as an indirect probe of functional changes in photoreceptor oxygen consumption. "
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    ABSTRACT: Rod cell oxidative stress is a major pathogenic factor in retinal disease, such as diabetic retinopathy (DR) and retinitis pigmentosa (RP). Personalized, non-destructive, and targeted treatment for these diseases remains elusive since current imaging methods cannot analytically measure treatment efficacy against rod cell compartment-specific oxidative stress in vivo. Over the last decade, novel MRI-based approaches that address this technology gap have been developed. This review summarizes progress in the development of MRI since 2006 that enables earlier evaluation of the impact of disease on rod cell compartment-specific function and the efficacy of anti-oxidant treatment than is currently possible with other methods. Most of the new assays of rod cell compartment-specific function are based on endogenous contrast mechanisms, and this is expected to facilitate their translation into patients with DR and RP, and other oxidative stress-based retinal diseases.
    Progress in Retinal and Eye Research 09/2015; DOI:10.1016/j.preteyeres.2015.09.001 · 8.73 Impact Factor
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    • "Retinal neurodegeneration has also been identified in diabetic rodent models, which reproduces most aspects of the early stages of DR. Lewis rats with streptozotocin-induced type 1 diabetes have shown the most accelerated loss of retinal ganglion cells (RGCs) at 8 months after the onset of diabetes [13]. The spontaneous development of diabetes in Ins2Akita mice for 5-6 months also reveals the changes in neurosensory retina, including RGCs apoptosis as well as marked alterations to the morphology of surviving cells, reduction of cholinergic and dopaminergic amacrine cells, and a distinct thinning of the inner plexiform layer and the inner nuclear layer [14] [15] [16]. "
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    ABSTRACT: Purpose. To describe both the functional and pathological alternations in neurosensory retina in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods. db/db (BKS/DB-/-) mice and heterozygous littermates (as control group) at various ages (12, 16, 20, 24, and 28 weeks) were inspected with pattern electroretinogram (PERG), fundus fluorescein angiography (FFA), and optical coherence tomography (OCT). Histological markers of neuroinflammation (IBA-1 and F4/80) were evaluated by immunohistochemistry. In addition, levels of retinal ganglion cell death were measured by terminal dUTP nick-end labeling (TUNEL). Results. Significant alternations of PERG responses and increased retinal ganglion cells (RGCs) apoptosis were observed in diabetic db/db mice for 20-week period when compared with control group. IBA-1 and F4/80 expression in microglia/macrophages became evidently for 24-week period, thus supporting the PERG findings. Furthermore, obvious thinning of nasal and dorsal retina in 28-week-old db/db mice was also revealed by OCT. No visible retinal microvascular changes were detected by FFA throughout the experiments on db/db mice. Conclusions. Diabetic retina underwent neurodegenerative changes in db/db mice, which happened at retinal ganglion cell layer and inner nuclear layer. But there was no obvious abnormality in retinal vasculature on db/db mice.
    Journal of Ophthalmology 03/2015; 2015:757412. DOI:10.1155/2015/757412 · 1.43 Impact Factor
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    • "Therefore, our findings, especially with the retinal-specific ERG results and the use of rTHKO mice, corroborate the role of diminished retinal DA bioavailability in visual dysfunction. The effect is unlikely due to degeneration of retinal neurons because the examined time points were before reports of retinal degeneration in diabetes (Martin et al., 2004; Kern et al., 2010b; Villarroel et al., 2010; Barber et al., 2011). Furthermore, no evidence of retinal degeneration was observed due to deletion of Th in the original characterization of the rTHKO mice (Jackson et al., 2012). "
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    ABSTRACT: Dopamine (DA) functions as an essential neuromodulator in the brain and retina such that disruptions in the dopaminergic system are associated with common neurologic disorders such as Parkinson's disease. Although a reduction in DA content has been observed in diabetes, its effects in the development of diabetes-induced neuropathy remains unknown. Because the retina is rich in DA and has a well known diabetes-induced pathology (diabetic retinopathy or DR), this study was designed to examine the role of retinal DA deficiency in early visual defects in DR. Using rodent models of type 1 diabetes mellitus, we investigated whether diabetes caused a reduction in retinal DA content in both rats and mice and determined whether restoring DA levels or activating specific DA receptor pathways could improve visual function (evaluated with optokinetic tracking response) of diabetic mice, potentially via improvement of retinal function (assessed with electroretinography). We found that diabetes significantly reduced DA levels by 4 weeks in rats and by 5 weeks in mice, coincident with the initial detection of visual deficits. Treatment with l-DOPA, a DA precursor, improved overall retinal and visual functions in diabetic mice and acute treatment with DA D1 or D4 receptor agonists improved spatial frequency threshold or contrast sensitivity, respectively. Together, our results indicate that retinal DA deficiency is an underlying mechanism for early, diabetes-induced visual dysfunction and suggest that therapies targeting the retinal dopaminergic system may be beneficial in early-stage DR.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2014; 34(3):726-36. DOI:10.1523/JNEUROSCI.3483-13.2014 · 6.34 Impact Factor
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