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dc.contributor.authorIbrahim, Ahmed S.
dc.contributor.authorEl-Remessy, Azza B.
dc.contributor.authorMatragoon, Suraporn
dc.contributor.authorZhang, Wenbo
dc.contributor.authorPatel, Yogin
dc.contributor.authorKhan, Sohail
dc.contributor.authorAl-Gayyar, Mohammed M H
dc.contributor.authorEl-Shishtawy, Mamdouh M.
dc.contributor.authorLiou, Gregory I.
dc.date.accessioned2012-10-26T16:26:58Z
dc.date.available2012-10-26T16:26:58Z
dc.date.issued2011-03-22en_US
dc.identifier.citationDiabetes. 2011 Apr 22; 60(4):1122-1133en_US
dc.identifier.issn1939-327Xen_US
dc.identifier.pmid21317295en_US
dc.identifier.doi10.2337/db10-1160en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/644
dc.description.abstractOBJECTIVE: During diabetes, retinal microglial cells are activated to release inflammatory cytokines that initiate neuronal loss and bloodâ retinal barrier breakdown seen in diabetic retinopathy (DR). The mechanism by which diabetes activates microglia to release those inflammatory mediators is unclear and was therefore elucidated.
dc.description.abstractRESEARCH DESIGN AND METHODS: Microglia activation was characterized in streptozocin-injected rats and in isolated microglial cells using immunofluorescence, enzyme-linked immunosorbent assay, RT-PCR, and Western blot analyses.
dc.description.abstractRESULTS: In 8-week diabetic retina, phospho-extracellular signalâ related kinase (ERK) and P38 mitogen-activated protein kinases were localized in microglia, but not in Mueller cells or astrocytes. At the same time, Amadori-glycated albumin (AGA)-like epitopes were featured in the regions of microglia distribution, implicating a pathogenic effect on microglial activation. To test this, diabetic rats were treated intravitreally with A717, a specific AGA-neutralizing antibody, or murine IgG. Relative to nondiabetic rats, diabetic rats (IgG-treated) manifested 3.9- and 7.9-fold increases in Iba-1 and tumor necrosis factor (TNF)-α mRNAs, respectively. Treatment of diabetic rats with A717 significantly attenuated overexpression of these mRNAs. Intravitreal injection of AGA per se in normal rats resulted in increases of Iba-1 expression and TNF-α release. Guided by these results, a cultured retinal microglia model was developed to study microglial response after AGA treatment and the mechanistic basis behind this response. The results showed that formation of reactive oxygen species and subsequent activation of ERK and P38, but not Jun NH2-terminal kinase, are molecular events underpinning retinal microglial TNF-α release during AGA treatment.
dc.description.abstractCONCLUSIONS: These results provide new insights in understanding the pathogenesis of early DR, showing that the accumulated AGA within the diabetic retina elicits the microglial activation and secretion of TNF-α. Thus, intervention trials with agents that neutralize AGA effects may emerge as a new therapeutic approach to modulate early pathologic pathways long before the occurrence of vision loss among patients with diabetes.
dc.rights© 2011 by the American Diabetes Association.en_US
dc.subjectSignal Transductionen_US
dc.titleRetinal Microglial Activation and Inflammation Induced by Amadori-Glycated Albumin in a Rat Model of Diabetesen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3064086en_US
dc.contributor.corporatenameDepartment of Ophthalmology
dc.contributor.corporatenameVision Discovery Institute
dc.contributor.corporatenameVascular Biology Center
dc.contributor.corporatenameDepartment of Medicine
refterms.dateFOA2019-04-10T00:23:48Z
html.description.abstractOBJECTIVE: During diabetes, retinal microglial cells are activated to release inflammatory cytokines that initiate neuronal loss and bloodâ retinal barrier breakdown seen in diabetic retinopathy (DR). The mechanism by which diabetes activates microglia to release those inflammatory mediators is unclear and was therefore elucidated.
html.description.abstractRESEARCH DESIGN AND METHODS: Microglia activation was characterized in streptozocin-injected rats and in isolated microglial cells using immunofluorescence, enzyme-linked immunosorbent assay, RT-PCR, and Western blot analyses.
html.description.abstractRESULTS: In 8-week diabetic retina, phospho-extracellular signalâ related kinase (ERK) and P38 mitogen-activated protein kinases were localized in microglia, but not in Mueller cells or astrocytes. At the same time, Amadori-glycated albumin (AGA)-like epitopes were featured in the regions of microglia distribution, implicating a pathogenic effect on microglial activation. To test this, diabetic rats were treated intravitreally with A717, a specific AGA-neutralizing antibody, or murine IgG. Relative to nondiabetic rats, diabetic rats (IgG-treated) manifested 3.9- and 7.9-fold increases in Iba-1 and tumor necrosis factor (TNF)-α mRNAs, respectively. Treatment of diabetic rats with A717 significantly attenuated overexpression of these mRNAs. Intravitreal injection of AGA per se in normal rats resulted in increases of Iba-1 expression and TNF-α release. Guided by these results, a cultured retinal microglia model was developed to study microglial response after AGA treatment and the mechanistic basis behind this response. The results showed that formation of reactive oxygen species and subsequent activation of ERK and P38, but not Jun NH2-terminal kinase, are molecular events underpinning retinal microglial TNF-α release during AGA treatment.
html.description.abstractCONCLUSIONS: These results provide new insights in understanding the pathogenesis of early DR, showing that the accumulated AGA within the diabetic retina elicits the microglial activation and secretion of TNF-α. Thus, intervention trials with agents that neutralize AGA effects may emerge as a new therapeutic approach to modulate early pathologic pathways long before the occurrence of vision loss among patients with diabetes.


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