Studies on the Retina of the Diabetic db/db Mouse

Midena, Edoardo; Segato, Tatiana; Radin, S; Giorgio, G. Di; Meneghini, Francesca; Piermarocchi, Stefano; Belloni, Anna S.

doi:10.1159/000266787

Cited by 69 publications

(51 citation statements)

References 20 publications

(24 reference statements)

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“…These observations strongly suggest that subnormal superior hemiretinal ⌬PO 2 is an early functional lesion that predicts the development of the structural lesions. The vascular lesions of diabetic retinopathy in rats or mice take longer to develop than the 3-to 4-month duration used in the present study (7,23,24), so we cannot currently evaluate the relation of NO to the development of histopathology. It was beyond the scope of this study to determine why the superior hemiretinal ⌬PO 2 becomes subnormal and the inferior hemiretinal does not.…”

Section: Discussionmentioning

confidence: 88%

Regulation of the Early Subnormal Retinal Oxygenation Response in Experimental Diabetes by Inducible Nitric Oxide Synthase

et al. 2004

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We aimed to test the hypothesis that the inducible form of nitric oxide synthase (iNOS) contributes to the development of an early subnormal retinal oxygenation response in preclinical models of diabetic retinopathy. In urethane anesthetized Sprague Dawley rats or C57BL/6 mice, functional magnetic resonance imaging was used to noninvasively measure the change in retinal oxygen tension (⌬PO 2 ) during a carbogen-inhalation challenge. In the rat experiments, the retinal ⌬PO 2 of the following groups were compared: control rats (n ‫؍‬ 9), 3-month diabetic rats (n ‫؍‬ 5), and 3-month diabetic rats treated orally with L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide, a prodrug of an inhibitor of iNOS (n ‫؍‬ 6). In addition, the retinal ⌬PO 2 of the following mouse groups were compared: C57BL/6 mice (n ‫؍‬ 20), C57BL/6-Nos2 tm1Lau mice (n ‫؍‬ 10), 4-month diabetic mice (n ‫؍‬ 13), and 4-month diabetic knockout mice (n ‫؍‬ 6). Only the ⌬PO 2 of the superior hemiretina of the diabetic rat and mice groups were significantly subnormal (P < 0.05). The superior ⌬PO 2 of the diabetic rats treated with the prodrug was not significantly (P > 0.05) different from their respective normal controls. In the mice experiments, the superior retinal ⌬PO 2 of the iNOS null mice was not statistically different (P > 0.05) from that of normal control mice. iNOS is required for the development of an early subnormal ⌬PO 2 in experimental diabetic retinopathy. Diabetes 53: [173][174][175][176][177][178] 2004 N itric oxide (NO), a potent regulator of retinal vascular function, is elevated in the vitreous humor of patients with proliferative diabetic retinopathy and with tractional retinal detachment, as well as in the retina of rodents, 2-4 months after the induction of diabetes (1-4). NO synthase (NOS) converts L-arginine to NO and L-citrulline. Excessive NO production by the inducible isoform of NOS (iNOS) in particular has been implicated in the pathogenesis of various ocular diseases (5,6). iNOS is induced in the retina in diabetes, but it is not yet known if iNOS regulates aspects of retinal circulatory pathophysiology associated with diabetes (4).Previously, we developed a novel functional magnetic resonance imaging (MRI) method for measuring the retinal oxygenation response to a hyperoxic inhalation challenge in the newborn and adult rat, rabbit, cat, and human (7-10). In this technique, hyperoxia increases vitreous partial oxygen pressure over room-air values (⌬PO 2 ). Because oxygen is paramagnetic, this ⌬PO 2 will produce an increase in the vitreous signal intensity on a T 1 -weighted image. Furthermore, good agreement is found between the MRI-measured response and that determined by other investigators (11) using an oxygen electrode in normal rat retina under similar conditions. In normal adult and newborn rats, carbogen breathing oxygenated the retina significantly better than pure oxygen breathing (11). Carbogen is a gas mixture of carbon dioxide (5%) and oxygen (95%) that has been used clinically, instead of 100% oxygen, to minim...

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Section: Discussionmentioning

confidence: 88%

Regulation of the Early Subnormal Retinal Oxygenation Response in Experimental Diabetes by Inducible Nitric Oxide Synthase

et al. 2004

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“…While ERG can be useful to evaluate the impact of an antioxidant on diabetesinduced rod dysfunction, ERG provide no spatial resolution. [55][56][57][58][59] Multifocal ERG can distinguish electrical responses from different regions panretinally but suffers from extensive light scattering in small rodent eyes. 60,61 To address these problems, a new approach has been developed (and used herein) that examines responses from a small piece of retina ex vivo (i.e., transretinal recordings).…”

Section: Discussionmentioning

confidence: 99%

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Berkowitz

Kern

Bissig

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Diabetes appears to induce a visual cycle defect because rod dysfunction is correctable with systemic treatment of the visual cycle chromophore 11-cis-retinaldehyde. However, later studies have found no evidence for visual cycle impairment. Here, we further examined whether photoreceptor dysfunction is corrected with 11-cis-retinaldehyde. Because antioxidants correct photoreceptor dysfunction in diabetes, the hypothesis that exogenous visual chromophores have antioxidant activity in the retina of diabetic mice in vivo was tested.METHODS. Rod function in 2-month-old diabetic mice was evaluated using transretinal electrophysiology in excised retinas and apparent diffusion coefficient (ADC) MRI to measure light-evoked expansion of subretinal space (SRS) in vivo. Optokinetic tracking was used to evaluate cone-based visual performance. Retinal production of superoxide free radicals, generated mostly in rod cells, was biochemically measured with lucigenin. Diabetic mice were systemically treated with a single injection of either 11-cis-retinaldehyde, 9-cisretinaldehyde (a chromophore surrogate), or all-trans-retinaldehyde (the photoisomerization product of 11-cis-retinaldehyde).RESULTS. Consistent with previous reports, diabetes significantly reduced (1) dark-adapted rod photo responses (transretinal recording) by~18%, (2) rod-dominated light-stimulated SRS expansion (ADC MRI) by~21%, and (3) cone-dominated contrast sensitivity (using optokinetic tracking [OKT]) by~30%. Both 11-cis-retinaldehyde and 9-cis-retinaldehyde largely corrected these metrics of photoreceptor dysfunction. Higher-than-normal retinal superoxide production in diabetes by~55% was also significantly corrected following treatment with 11-cis-retinaldehyde, 9-cis-retinaldehyde, or all-trans-retinaldehyde.CONCLUSIONS. Collectively, data suggest that retinaldehydes improve photoreceptor dysfunction in diabetic mice, independent of the visual cycle, via an antioxidant mechanism.

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“…Investigations of DR and neurodegeneration in Lepr db/db mice have been performed for nearly 25 years (Cheung et al 2005;Lai and Lo 2013;Midena et al 1989;Robinson et al 2012). Although structural abnormalities, including reductions in thickness of the retina and RPE basement membrane, have been identified (Clements et al 1998;Tang et al 2011), only one study conducted a functional assessment of the BKS.Lepr model (Bogdanov et al 2014).…”

Section: Type 2 Diabetic Micementioning

confidence: 99%

Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes

Samuels

Bell

Pereira

et al. 2015

Journal of Neurophysiology

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Samuels IS, Bell BA, Pereira A, Saxon J, Peachey NS. Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes. J Neurophysiol 113: 1085-1099, 2015. First published November 26, 2014 doi:10.1152/jn.00761.2014In the diabetic retina, cellular changes in the retinal pigment epithelium (RPE) and neurons occur before vision loss or diabetic retinopathy can be identified clinically. The precise etiologies of retinal pathology are poorly defined, and it remains unclear if the onset and progression of cellular dysfunction differ between type 1 and type 2 diabetes. Three mouse models were used to compare the time course of RPE involvement in type 1 and type 2 diabetes. C57BL/6J mice injected with streptozotocin (STZ mice) modeled type 1 diabetes, whereas Lepr db/db mice on both BKS and B6.BKS background strains modeled type 2 diabetes. Electroretinogram (ERG)-based techniques were used to measure light-evoked responses of the RPE (direct current-coupled ERG, dc-ERG) and the neural retina (a-wave, b-wave). Following onset of hyperglycemia, a-wave and b-wave amplitudes of STZ mice declined progressively and by equivalent degrees. Components of the dc-ERG were also altered, with the largest reduction seen in the c-wave. Lepr db/db mice on the BKS strain (BKS.Lepr) displayed sustained hyperglycemia and a small increase in insulin, whereas Lepr db/db mice on the B6.BKS background (B6.BKS.Lepr) were transiently hyperglycemic and displayed severe hyperinsulinemia. BKS.Lepr mice exhibited sustained reductions in the dc-ERG c-wave, fast oscillation, and off response that were not attributable to reduced photoreceptor activity; B6.BKS.Lepr mice displayed transient reductions in the c-wave and fast oscillation that correlated with hyperglycemia and magnitude of photoreceptor activity. In summary, all mouse models displayed altered RPE function concomitant with the onset of hyperglycemia. These results suggest that RPE function is directly reduced by elevated blood glucose levels. That RPE dysfunction was reversible and mitigated in hyperinsulinemic B6.BKS.Lepr mice provides insight into the underlying mechanism.

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Studies on the Retina of the Diabetic db/db Mouse

Cited by 69 publications

References 20 publications

Regulation of the Early Subnormal Retinal Oxygenation Response in Experimental Diabetes by Inducible Nitric Oxide Synthase

Regulation of the Early Subnormal Retinal Oxygenation Response in Experimental Diabetes by Inducible Nitric Oxide Synthase

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Early retinal pigment epithelium dysfunction is concomitant with hyperglycemia in mouse models of type 1 and type 2 diabetes

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