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C. Patel, W. Zhang, B. Baban, M. Rojas, G. I. Liou, R. W. Caldwell, R. B. Caldwell; Role of Arginase in Oxidative Stress in Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5640.
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Recent studies have identified increases in vascular arginase and in many disease conditions characterized by vascular dysfunction. It is also reported that increased arginase activity in diabetes causes vascular endothelial dysfunction by uncoupling NOS, which reduces bioavailable NO levels and increases reactive oxygen species. However, the role of arginase in causing oxidative stress in the vasculature of the retina, more specifically in diabetic retinopathy has not been studied.
Experiments were performed in retinal endothelial and microglia cells treated with high glucose (25 or 35 mM) and AGE (500 ug/ml) respectively. Retinas of STZ-induced diabetic mice were also used for flow cytometry analysis and to assess nitrate and nitrite levels. Retinas of the diabetic arginase knockout mice haplo-insufficient in arginase 1 and completely deficient in arginase 2 (A1+/-A2-/-) were also used to study nitrate and nitrite levels and superoxide formation.
These studies showed that arginase 1 (A1) and iNOS mRNA levels were significantly increased in retinal microglia cells treated with glycated-albumin (an advanced glycation end product). Arginase 2 (A2) mRNA levels were not affected. Flow cytometry analyses of cells from STZ-diabetic mice (1 month) indicated that A1 is increased in retinal glia and activated microglia/macrophages and blood monocytes and neutrophils and these effects were correlated with diabetes-induced increases in expression of inflammatory markers, VEGF and MCP-1. Diabetes or high glucose increased arginase activity and decreased NO levels in retinal endothelial cells, and this decline in NO was blocked by the arginase inhibitor S-2-boronethyl-L-cysteine. In addition, diabetes-induced decreases in NO levels and increases in oxidative stress were abrogated in arginase knockout (A1+/-A2-/-) mice.
These studies indicate that diabetes or high glucose-induced oxidative stress is correlated with elevated arginase activity, NOS uncoupling, decreased NO bioavailability, and increased retinal inflammation.
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