Early Retinal Damage in Experimental Diabetes: Electroretinographical and Morphological Observations

Li, Q.; Zemel, Esther; Miller, Benjamin; Perlman, Ido

doi:10.1006/exer.2002.1170

Cited by 198 publications

(174 citation statements)

References 46 publications

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“…2). OP changes including the reduced amplitude and prolonged implicit time are known to occur in the early stage of murine and human diabetic retinopathy (1,2,20,21). There was no remarkable difference in a-or b-wave among nondiabetes and 4-week diabetes treated with vehicle, telimsartan, and valsartan (data not shown).…”

Section: At1r-mediated Retinal Dysfunction In Diabetesmentioning

confidence: 87%

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

et al. 2008

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OBJECTIVE-Pathogenic mechanisms underlying diabetesinduced retinal dysfunction are not fully understood. The aim of the present study was to show the relationship of the reninangiotensin system (RAS) with the synaptic vesicle protein synaptophysin and neuronal activity in the diabetic retina.RESEARCH DESIGN AND METHODS-C57BL/6 mice with streptozotocin-induced diabetes were treated with the angiotensin II type 1 receptor (AT1R) blocker telimsartan or valsartan, and retinal function was analyzed by electroretinography. Retinal production of the RAS components and phosphorylation of ERK (extracellular-signal regulated kinase) were examined by immunoblotting. Retinal mRNA and protein levels of synaptophysin were measured by quantitative RT-PCR and immunoblot analyses, respectively. In vitro, synaptophysin levels were also evaluated using angiotensin II-stimulated PC12D neuronal cells cultured with or without the inhibition of ERK signaling or the ubiquitin-proteasome system (UPS).RESULTS-Induction of diabetes led to a significant increase in retinal production of angiotensin II and AT1R together with ERK activation in the downstream of AT1R. AT1R blockade significantly reversed diabetes-induced electroretinography changes and reduction of synaptophysin protein, but not mRNA, levels in the diabetic retina. In agreement with the AT1R-mediated posttranscriptional downregulation of synaptophysin in vivo, in vitro application of angiotensin II to PC12D neuronal cells caused the UPS-mediated degradation of synaptophysin protein via AT1R, which proved to be induced by ERK activation.CONCLUSIONS-These data indicate the first molecular evidence of the RAS-induced synaptophysin degradation and neuronal dysfunction in the diabetic retina, suggesting the possibility of the AT1R blockade as a novel neuroprotective treatment for diabetic retinopathy.

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Section: At1r-mediated Retinal Dysfunction In Diabetesmentioning

confidence: 87%

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

et al. 2008

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“…Many of these studies have been undertaken in the streptozotocin (STZ) rat model of type-1 diabetes. Neuronal dysfunction in terms of attenuated and delayed ERG responses occurs as early as 2 weeks after the induction of hyperglycaemia in rats [14,15]. Moreover, inner retinal function (i.e.…”

Section: Introductionmentioning

confidence: 99%

“…oscillatory potentials and scotopic threshold responses) is more sensitive to hyperglycaemia than is the outer retinal component in STZ-induced diabetes [16]. It is of interest that Li et al [15] report that the ERG b-wave was reduced by 2 weeks after diabetes induction, which was well before a detectable increase in glial fibrillary acidic protein expression in Müller cell end feet (6 weeks). These data suggest that dysfunction of inner retinal neurons precedes glial changes in diabetic rats.…”

Section: Introductionmentioning

confidence: 99%

Glial and neuronal dysfunction in streptozotocin-induced diabetic rats

Wong

Vingrys

Bui

2011

j ocul biol dis inform

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Neuronal dysfunction has been noted very soon after the induction of diabetes by streptozotocin injection in rats. It is not clear from anatomical evidence whether glial cell dysfunction accompanies the well-documented neuronal deficit. Here, we isolate the Müller cell driven slow-P3 component of the full-field electroretinogram and show that it is attenuated at 4 weeks following the onset of streptozotocin-hyperglycaemia. We also found a concurrent reduction in the sensitivity of the phototransduction cascade, as well as in the components of the electroretinogram known to indicate retinal ganglion cell and amacrine cell integrity. Our data support the idea that neuronal and Müller cell dysfunction occurs at the same time in streptozotocin-induced hyperglycaemia.

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“…When occurring together, these changes may explain some of the functional deficits in vision appearing in diabetes before the onset of vascular abnormalities. In fact, abnormal electroretinograms have been found in patients with type 1 diabetes previous to the development of clinically detectable vascular retinal pathology (4), as well as in rats at short time intervals after the onset of experimental diabetes (5).…”

mentioning

confidence: 99%

Lower Somatostatin Expression Is an Early Event in Diabetic Retinopathy and Is Associated With Retinal Neurodegeneration

Carrasco

Hernández²,

Miralles³

et al. 2007

Diabetes Care

194

149

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OBJECTIVE -To test the hypothesis that a reduction of somatostatin (SST) in the retina exists in patients without clinically detectable diabetic retinopathy and that it is associated with retinal neurodegeneration.RESEARCH DESIGN AND METHODS -Human diabetic postmortem eyes (n ϭ 10) without clinically detectable retinopathy were compared with eyes (n ϭ 10) from nondiabetic donors. SST mRNA (RT-PCR) and SST-28 immunoreactivity (confocal laser) were measured separately in neuroretina and retinal pigment epithelium (RPE). In addition, SST-28 (radioimmunoassay) was measured in the vitreous fluid. Glial fibrillar acidic protein (GFAP) was assessed by immunofluorescence and Western blot. Apoptotic cells were quantified using transferasemediated dUTP nick-end labeling.RESULTS -A higher expression of SST was detected in RPE than neuroretina in both groups. SST mRNA levels and SST-28 immunoreactivity were significantly lower in both RPE and the neuroretina from diabetic donors compared with nondiabetic donors. These results were in agreement with those obtained by measuring SST-28 in the vitreous fluid of the same donors. Increased GFAP and a higher degree of apoptosis were observed in diabetic retinas compared with nondiabetic retinas. These changes were most evident in patients with the higher deficit of SST.CONCLUSIONS -Underproduction of SST is an early event in the eyes of diabetic patients and is associated with glial activation and neural death. In addition, our results suggest that RPE is an important source of SST in the human eye. The possible role of the lower production of SST in the pathogenesis of diabetic retinopathy requires further investigation. Diabetes Care 30:2902-2908, 2007D iabetic retinopathy is the most common complication of diabetes and remains the leading cause of new blindness among working-age individuals in developed countries (1). Although diabetic retinopathy has been traditionally viewed as a disorder of retinal vasculature, retinal neurodegeneration may be a primary pathology that gives rise to microvascular changes (2,3). The degenerative changes in the neuroretina include increased apoptosis, glial cell reactivity, microglial activation, and altered glutamate metabolism. When occurring together, these changes may explain some of the functional deficits in vision appearing in diabetes before the onset of vascular abnormalities. In fact, abnormal electroretinograms have been found in patients with type 1 diabetes previous to the development of clinically detectable vascular retinal pathology (4), as well as in rats at short time intervals after the onset of experimental diabetes (5).Somatostatin (SST) is a widely distributed peptide, and its diverse biological functions include neurotransmission and antisecretory and antiproliferative activities (6). SST and its receptors are found in the neuroretina of various species, including humans, and growing evidence suggests that in the retina, SST acts both as a neuromodulator and antiangiogenic factor (7). SST production in the human retina ha...

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Early Retinal Damage in Experimental Diabetes: Electroretinographical and Morphological Observations

Cited by 198 publications

References 46 publications

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

Glial and neuronal dysfunction in streptozotocin-induced diabetic rats

Lower Somatostatin Expression Is an Early Event in Diabetic Retinopathy and Is Associated With Retinal Neurodegeneration

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