An Integrated Approach to Diabetic Retinopathy Research

Gardner, Thomas W.

doi:10.1001/archophthalmol.2010.362

Cited by 85 publications

(63 citation statements)

References 39 publications

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“…However, a growing body of evidence suggests that a neuropathy also exists in diabetic retina, perhaps even before overt nonperfusion of the neuropile. This broadening perspective has heightened the understanding of neuronal dysfunction and neurodegeneration and their corresponding clinical features, such as loss of color vision (68) and contrast sensitivity (69) and reduced electrical responses on electroretinographic testing (70,71) that can occur before overt microvascular changes. Apoptotic death of retinal ganglion cells (RGC) and amacrine cells occurs in diabetic animal models (72) and has also been observed clinically in postmortem diabetic eyes (73,74).…”

Section: The Neurovascular Unit: a Framework For Understanding Drmentioning

confidence: 99%

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

Duh¹,

Sun²,

Stitt³

2017

JCI Insight

759

648

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Section: The Neurovascular Unit: a Framework For Understanding Drmentioning

confidence: 99%

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

Duh¹,

Sun²,

Stitt³

2017

JCI Insight

759

648

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“…Recently, proinflammatory lipids, 13 epigenetic and epigenomic modifications, 14 insulin dysregulation, 15 and b-cellulin signaling, 16 which initiate and contribute to DR pathogenesis independently from hyperglycemic condition, have been identified. biochemical pathways and inflammation in diabetic retinopathy (DR) pathogenesis.…”

Section: Mechanisms Implicated In the Pathogenesis Of Drmentioning

confidence: 99%

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Roy

Kern

Song

et al. 2017

The American Journal of Pathology

165

147

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Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina. Sustained inflammation induces biochemical and molecular changes, ultimately contributing to retinal complications and vision loss in diabetic retinopathy. In this review, we describe changes involving metabolic abnormalities secondary to hyperglycemia, oxidative stress, and activation of transcription factors, together with neuroglial alterations in the diabetic retina. Changes in biochemical pathways and how they promote pathophysiologic developments involving proinflammatory cytokines, chemokines, and adhesion molecules are discussed. Inflammation-mediated leukostasis, retinal ischemia, and neovascularization and their contribution to pathological and clinical stages leading to vision loss in diabetic retinopathy (DR) are highlighted. In addition, potential treatment strategies involving fibrates, connexins, neuroprotectants, photobiomodulation, and anti-inflammatory agents against the development and progression of DR lesions are reviewed. The importance of appropriate animal models for testing novel strategies against DR lesions is discussed; in particular, a novel nonhuman primate model of DR and the suitability of rodent models are weighed. The purpose of this review is to highlight our current understanding of the pathogenesis of DR and to summarize recent advances using novel approaches or targets to investigate and inhibit the retinopathy. (Am J Pathol 2017, 187: 9e19; http://dx

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“…DIABETIC RETINOPATHY IS BOTH the most common cause of legal blindness in working-age adults (reviewed by Gardner et al 2011) and one of the most common complications of diabetes mellitus (henceforth referred to as diabetes). Although traditionally considered a microvascular disease, there is increasing evidence that diabetic retinopathy partially involves a dysfunction of the neural retina that precedes the microvascular pathology typically observed at later stages of the disease (Antonetti et al 2006;Simó and Hernández 2014).…”

mentioning

confidence: 99%

Diabetic hyperglycemia reduces Ca²⁺ permeability of extrasynaptic AMPA receptors in AII amacrine cells

Castilho

Madsen

Ambrósio

et al. 2015

Journal of Neurophysiology

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Castilho Á, Madsen E, Ambrósio AF, Veruki ML, Hartveit E. Diabetic hyperglycemia reduces Ca 2ϩ permeability of extrasynaptic AMPA receptors in AII amacrine cells. J Neurophysiol 114: 1545-1553, 2015. First published July 8, 2015 doi:10.1152/jn.00295.2015.-There is increasing evidence that diabetic retinopathy is a primary neuropathological disorder that precedes the microvascular pathology associated with later stages of the disease. Recently, we found evidence for altered functional properties of synaptic ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in A17, but not AII, amacrine cells in the mammalian retina, and the observed changes were consistent with an upregulation of the GluA2 subunit, a key determinant of functional properties of AMPA receptors, including Ca 2ϩ permeability and current-voltage (I-V) rectification properties. Here, we have investigated functional changes of extrasynaptic AMPA receptors in AII amacrine cells evoked by diabetes. With patch-clamp recording of nucleated patches from retinal slices, we measured Ca 2ϩ permeability and I-V rectification in rats with ϳ3 wk of streptozotocin-induced diabetes and age-matched, noninjected controls. Under bi-ionic conditions (extracellular Ca 2ϩ concentration ϭ 30 mM, intracellular Cs ϩ concentration ϭ 171 mM), the reversal potential (E rev ) of AMPA-evoked currents indicated a significant reduction of Ca 2ϩ permeability in diabetic animals [E rev ϭ Ϫ17.7 mV, relative permeability of Ca 2ϩ compared with Cs ϩ (P Ca /P Cs ) ϭ 1.39] compared with normal animals (E rev ϭ Ϫ7.7 mV, P Ca /P Cs ϭ 2.35). Insulin treatment prevented the reduction of Ca 2ϩ permeability. I-V rectification was examined by calculating a rectification index (RI) as the ratio of the AMPA-evoked conductance at ϩ40 and Ϫ60 mV. The degree of inward rectification in patches from diabetic animals (RI ϭ 0.48) was significantly reduced compared with that in normal animals (RI ϭ 0.30). These results suggest that diabetes evokes a change in the functional properties of extrasynaptic AMPA receptors of AII amacrine cells. These changes could be representative for extrasynaptic AMPA receptors elsewhere in AII amacrine cells and suggest that synaptic and extrasynaptic AMPA receptors are differentially regulated.

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An Integrated Approach to Diabetic Retinopathy Research

Cited by 85 publications

References 39 publications

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Diabetic hyperglycemia reduces Ca²⁺ permeability of extrasynaptic AMPA receptors in AII amacrine cells

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An Integrated Approach to Diabetic Retinopathy Research

Cited by 85 publications

References 39 publications

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Diabetic hyperglycemia reduces Ca2+ permeability of extrasynaptic AMPA receptors in AII amacrine cells

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Diabetic hyperglycemia reduces Ca²⁺ permeability of extrasynaptic AMPA receptors in AII amacrine cells