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A.W. Stitt, P. Canning, D.K. Hsu, F.–T. Liu, N. Quinn; Galectin–3 mediates advanced glycation endproduct (AGE)–induced breakdown of the blood–retinal barrier . Invest. Ophthalmol. Vis. Sci. 2004;45(13):3209.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Advanced glycation endproducts (AGEs) accumulate during diabetes and have been previously shown to induce leakage from the retinal microvasculature. Galectin–3 has been described as a component of the AGE–receptor complex and may control AGE–mediated effects on a variety of cells and tissues. Using galectin–3 deficient mice (gal–3–/–) we have examined the role of this receptor in breakdown of the inner blood retinal barrier (iBRB) during diabetic retinopathy. Methods: Two experimental models were used in the study. Firstly, diabetes was established in wild–type (WT) and gal–3–/– C57/BL6 mice with a single streptozocin injection (165mg/kg) for 3 weeks. Animals were assigned into non–diabetic and diabetic groups and pyridoxamine, an AGE–inhibitor, was orally administered to a sub–group of diabetic mice (1g/L). In a previously established, complementary model, non–diabetic WT and gal–3–/– mice received daily infusion of AGE–modified albumin or native albumin (10mg/kg) for 7days. In both experimental models, iBRB dysfunction was assessed by the Evans Blue leakage assay. Gene expression analysis of the tight junction component ZO–1 was also assessed by real–time RT–PCR and immunofluorescence staining of retinal flat–mounts. Results: When compared to controls, there was a fourfold increase in retinal microvascular permeability in diabetic WT mice (p<0.05) and this was returned to non–diabetic levels by pyridoxamine treatment. ZO–1 mRNA and protein was significantly down–regulated in diabetes, an effect abolished by pyridoxamine. In gal–3–/– animals there was no significant difference in permeability between diabetic and non–diabetic groups, suggesting a protective effect when gal–3 is absent. Compared to native–albumin, AGE–infusion caused significant breakdown of the iBRB (p<0.03) although there was no difference between WT and gal–3–/– mice. Conclusions: AGEs appear to induce significant retinal microvascular leakage in diabetic mice, an effect that can be prevented by the AGE–specific inhibitor pyridoxamine. iBRB compromise during diabetic retinopathy may be mediated, at least in part, by galectin–3.
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