Diabetes Alters Osmotic Swelling Characteristics and Membrane Conductance of Glial Cells in Rat Retina

Pannicke, Thomas; Iandiev, Ianors; Wurm, Antje; Uckermann, Ortrud; Hagen, Franziska vom; Reichenbach, Andreas; Wiedemann, Peter; Hammes, Hans‐Peter; Bringmann, Andreas

doi:10.2337/diabetes.55.03.06.db05-1349

Cited by 183 publications

(180 citation statements)

References 35 publications

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“…Thus, through osmotic coupling to the transglial K + currents, water moves through the Müller cell bodies from the retinal neuropile into the vitreous body and retinal capillaries [29]. Diabetes is associated with a downregulation and/or mislocalisation of Kir4.1 and aquaporin 4 channels in Müller glia [14,46]. These diabetes-related abnormalities were also observed in the current study and could disrupt the clearance of excess K + and water from the retina, thereby promoting oedematous changes and neuronal hyperexcitation with associated glutamate release [11].…”

Section: Discussionmentioning

confidence: 99%

“…A previous report by Pannicke et al [14] demonstrated diabetes-related alterations in the distribution pattern of Kir4.1 on Müller glia. In the current study, Kir4.1 immunoreactivity in retina from non-diabetic animals was predominantly localised to the inner retina, where it was strongly enriched in the end-feet and perivascular membranes of Müller cells (Fig.…”

Section: P<0001 Vs Dbmentioning

confidence: 99%

“…For example, Müller glia produce increased levels of glial fibrillary acidic protein (GFAP) [12] and show enhanced synthesis of glutamate with resultant retinal excitotoxicity [13]. Recent evidence also indicates that cytoplasmic swelling of Müller glia is a key factor in diabetes-related retinal oedema, a response that may be linked to K + ion imbalance [14]. Among many possible pathogenic mediators of retinal dysfunction is the formation of AGEs and advanced lipoxidation end-products (ALEs).…”

Section: Introductionmentioning

confidence: 99%

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Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

et al. 2010

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Aims/hypothesis The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it. Methods Sprague-Dawley rats were divided into three groups: (1) non-diabetic; (2) untreated streptozotocininduced diabetic; and (3) diabetic treated with the AGE/ ALE inhibitor pyridoxamine for the duration of diabetes. Rats were killed and their retinas were evaluated for neuroglial pathology. Results AGEs and ALEs accumulated at higher levels in diabetic retinas than in controls (p<0.001). AGE/ALE immunoreactivity was significantly diminished by pyridoxamine treatment of diabetic rats. Diabetes was also associated with the up-regulation of the oxidative stress marker haemoxygenase-1 and the induction of glial fibrillary acidic protein production in Müller glia (p<0.001). Pyridoxamine treatment of diabetic rats had a significant beneficial effect on both variables (p < 0.001). Diabetes also significantly altered the normal localisation of the potassium inwardly rectifying channel Kir4.1 and the water channel aquaporin 4 to the Müller glia end-feet interacting with retinal capillaries. These abnormalities were prevented by pyridoxamine treatment. Conclusions/interpretation While it is established that AGE/ALE formation in the retina during diabetes is linked to microvascular dysfunction, this study suggests that these pathogenic adducts also play a role in Müller glial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Section: P<0001 Vs Dbmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

et al. 2010

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“…4b and c). Another robust diabetesmediated response by the retinal Müller glia is the mislocalisation of the weakly inward rectifying K + channel Kir 4.1, which is typically localised in Müller glia end-feet and surrounding blood vessels [31]. In diabetic retina, Kir4.1 becomes less localised at the interface with the retinal blood vessels and reduced at the ILM [6,31].…”

Section: Glo1 Overexpression Reduces Retinal Ages During Diabetesmentioning

confidence: 99%

Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology

et al. 2011

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Aims/hypothesis Methylglyoxal (MG) is an important precursor for AGEs. Normally, MG is detoxified by the glyoxalase (GLO) enzyme system (including component enzymes GLO1 and GLO2). Enhanced glycolytic metabolism in many cells during diabetes may overpower detoxification capacity and lead to AGE-related pathology. Using a transgenic rat model that overexpresses GLO1, we investigated if this enzyme can inhibit retinal AGE formation and prevent key lesions of diabetic retinopathy. Methods Transgenic rats were developed by overexpression of full length GLO1. Diabetes was induced in wild-type (WT) and GLO1 rats and the animals were killed after 12 or 24 weeks of hyperglycaemia. N ε -(Carboxyethyl)lysine (CEL), N ε -(carboxymethyl)lysine (CML) and MG-derivedhydroimidazalone-1 (MG-H1) were determined by immunohistochemistry and by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MSMS).Müller glia dysfunction was determined by glial fibrillary acidic protein (GFAP) immunoreactivity and by spatial localisation of the potassium channel Kir4.1. Acellular capillaries were quantified in retinal flat mounts. Results GLO1 overexpression prevented CEL and MG-H1 accumulation in the diabetic retina when compared with WT diabetic counterparts (p<0.01). Diabetes-related increases in Müller glial GFAP levels and loss of Kir4.1 at the vascular end-feet were significantly prevented by GLO1 overexpression (p<0.05) at both 12-and 24-week time points. GLO1 diabetic animals showed fewer acellular capillaries than WT diabetic animals (p<0.001) at 24 weeks' diabetes.A.K. Berner, O. Brouwers and R. Pringle contributed equally to this study.Electronic supplementary material The online version of this article

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“…10,11 There is a thinning of the outer nuclear layer as diabetes progresses, 12 loss of dopaminergic neurons, 13 and B50% depletion of cells in the inner nuclear layer after 44 months experimental diabetes. 14 Glial cells also suffer during hyperglycaemia, 15 in particular the Mü ller macroglia which demonstrate increased expression of glial fibrillary acidic protein, 16 loss of osmotic balance associated with a decrease in K þ currents, 17 and concomitant synthesis/ release of glutamate (as a function of disruption of the glutamate transporter 18 ) which contributes to excitotoxicity in the retinal neuropile. 19 Although the retina suffers a neuroglial pathology during diabetes, the clinically observed intraretinal microvascular changes serve as the basis for classification into non-proliferative diabetic retinopathy and proliferative diabetic retinopathy.…”

Section: Introductionmentioning

confidence: 99%

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

Curtis

Gardiner

Stitt

2009

Eye

310

231

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Retinopathy is a major complication of diabetes mellitus and this condition remains a leading cause of blindness in the working population of developed countries. As diabetic retinopathy progresses a range of neuroglial and microvascular abnormalities develop although it remains unclear how these pathologies relate to each other and their net contribution to retinal damage. From a haemodynamic perspective, evidence suggests that there is an early reduction in retinal perfusion before the onset of diabetic retinopathy followed by a gradual increase in blood flow as the complication progresses. The functional reduction in retinal blood flow observed during early diabetic retinopathy may be additive or synergistic to proinflammatory changes, leucostasis and vasoocclusion and thus be intimately linked to the progressive ischaemic hypoxia and increased blood flow associated with later stages of the disease. In the current review a unifying framework is presented that explains how arteriolar dysfunction and haemodynamic changes may contribute to late stage microvascular pathology and vision loss in human diabetic retinopathy.

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Diabetes Alters Osmotic Swelling Characteristics and Membrane Conductance of Glial Cells in Rat Retina

Cited by 183 publications

References 35 publications

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

Protection against methylglyoxal-derived AGEs by regulation of glyoxalase 1 prevents retinal neuroglial and vasodegenerative pathology

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

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