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: 2.25). 01/2010; 16:2121-31.
Source: PubMed

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite many years of clinical and laboratory investigation, diabetic retinopathy remains the leading cause of vision impairment among working-aged people. Mouse models have been valuable tools in further understanding the pathophysiology of diabetic retinopathy and discovering and assessing new potential therapeutic agents. However, although numerous diabetic mouse models have been developed, none of these models replicates all the key features of human diabetic retinopathy. In this review, we summarize and update the list of mouse diabetic and diabetic-like models that have been generated.
    Drug Discovery Today Disease Models 01/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rod tetrameric arrestin 1 (tet-ARR1), stored in the outer nuclear layer/inner segments in the dark, modulates photoreceptor synaptic activity; light exposure stimulates a reduction via translocation to the outer segments for terminating G-protein coupled phototransduction signaling. Here, we test the hypothesis that intraretinal spin-lattice relaxation rate in the rotating frame (1/T1ρ), an endogenous MRI contrast mechanism, has high potential for evaluating rod tet-ARR1 and its reduction via translocation. Dark- and light-exposed mice (null for the ARR1 gene, overexpressing ARR1, diabetic, or wild type with or without treatment with Mn(2+), a calcium channel probe) were studied using 1/T1ρ MRI. Immunohistochemistry and single-cell recordings of the retinas were also performed. In wild-type mice with or without treatment with Mn(2+), 1/T1ρ of avascular outer retina (64% to 72% depth) was significantly (P < 0.05) greater in the dark than in the light; a significant (P < 0.05) but opposite pattern was noted in the inner retina (<50% depth). Light-evoked outer retina Δ1/T1ρ was absent in ARR1-null mice and supernormal in overexpressing mice. In diabetic mice, the outer retinal Δ1/T1ρ pattern suggested normal dark-to-light tet-ARR1 translocation and chromophore content, conclusions confirmed ex vivo. Light-stimulated Δ1/T1ρ in inner retina was linked to changes in blood volume. Our data support 1/T1ρ MRI for noninvasively assessing rod tet-ARR1 and its reduction via protein translocation, which can be combined with other metrics of retinal function in vivo.-Berkowitz, B. A., Gorgis, J., Patel, A., Baameur, F., Gurevich, V. V., Craft, C. M., Kefalov, V. J., Roberts, R. Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo.
    The FASEB Journal 10/2014; 29(2). · 5.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diabetic retinopathy (DR) impairs vision of patients with type 1 and type 2 diabetes, associated with vascular dysfunction and occlusion, retinal edema, hemorrhage, and inappropriate growth of new blood vessels. The recent success of biologic treatments targeting vascular endothelial growth factor (VEGF) demonstrates that treating the vascular aspects in the later stages of the disease can preserve vision in many patients. It would also be highly desirable to prevent the onset of the disease or arrest its progression at a stage preceding the appearance of overt microvascular pathologies. The progression of DR is not necessarily linear but may follow a series of steps that evolve over the course of multiple years. Abundant data suggest that diabetes affects the entire neurovascular unit of the retina, with an early loss of neurovascular coupling, gradual neurodegeneration, gliosis, and neuroinflammation occurring before observable vascular pathologies. In this article, we consider the pathology of DR from the point of view that diabetes causes measurable dysfunctions in the complex integral network of cell types that produce and maintain human vision.
    Annals of the New York Academy of Sciences 03/2014; · 4.38 Impact Factor

Full-text (3 Sources)

Available from
Jun 1, 2014