Retinal Microglial Activation and Inflammation Induced by Amadori-Glycated Albumin in a Rat Model of Diabetes
Open Access
- 22 March 2011
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 60 (4), 1122-1133
- https://doi.org/10.2337/db10-1160
Abstract
OBJECTIVE During diabetes, retinal microglial cells are activated to release inflammatory cytokines that initiate neuronal loss and blood–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. RESEARCH 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. RESULTS In 8-week diabetic retina, phospho-extracellular signal–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. CONCLUSIONS 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.Keywords
This publication has 49 references indexed in Scilit:
- Expression of Macrophage Colony-Stimulating Factor (M-CSF) and Its Receptor in Streptozotocin-Induced Diabetic RatsCurrent Eye Research, 2009
- Amelioration of Diabetes-Associated Abnormalities in the Vitreous Fluid by an Inhibitor of Albumin GlycationInvestigative Opthalmology & Visual Science, 2008
- Retinal ganglion cells in diabetesThe Journal of Physiology, 2008
- Salicylate-Based Anti-Inflammatory Drugs Inhibit the Early Lesion of Diabetic RetinopathyDiabetes, 2007
- Multiple molecular targets in cancer chemoprevention by curcuminThe AAPS Journal, 2006
- Amadori adducts activate nuclear factor‐κB‐related proinflammatory genes in cultured human peritoneal mesothelial cellsBritish Journal of Pharmacology, 2005
- A central role for inflammation in the pathogenesis of diabetic retinopathyThe FASEB Journal, 2004
- Nonsteroidal anti‐inflammatory drugs prevent early diabetic retinopathy via TNF‐α suppressionThe FASEB Journal, 2002
- ERK Mediates Effects of Glycated Albumin in Mesangial CellsBiochemical and Biophysical Research Communications, 2001
- Glycated Albumin Stimulates Fibronectin and Collagen IV Production by Glomerular Endothelial Cells under Normoglycemic ConditionsBiochemical and Biophysical Research Communications, 1997