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B. Baban, M. Romero, J. Iddings, G. Grant, T. Lemtalsi, R. B. Caldwell, R. W. Caldwell; Role of Arginase in Diabetes- and Endotoxin-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4906. doi: https://doi.org/.
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Vascular inflammation is critically involved in the pathogenesis of diabetic retinopathy. We have shown before that diabetes induced breakdown of the blood-retinal barrier involves uncoupling of endothelial nitric oxide synthase (eNOS), leading to increases in oxidative stress and VEGF expression. Our recent work indicates that diabetes-induced eNOS uncoupling and vascular dysfunction are mediated by increases in arginase expression/activity. Arginase competes with eNOS for their common substrate arginine, reducing NO formation and impairing vasorelaxation. Because eNOS-derived NO is also a potent anti-inflammatory mediator, we hypothesized that increases in arginase are also involved in retinal vascular inflammation.
We tested this concept using mouse models of steptozotocin-induced diabetes and endotoxin-induced retinopathy. Flow cytometry was performed to analyze arginase, VEGF and MCP-1 (Monocyte Chemotactic Protein) expression in blood cells, retinal astrocytes and microglial cells of wild-type and arginase knockout (KO) mice. Arginase activity was determined by an assay for conversion of arginine to urea.
We demonstrate that arginase, VEGF and MCP-1 expression in the blood and retina are increased significantly in murine models of both diabetes- and endotoxin-induced retinopathy as compared with the controls. Our results also show that in blood, neutrophils and macrophages, and in retina, macrophages, microglia and astrocytes are major sources of enhanced arginase, MCP-1 and VEGF expression. More importantly, our studies in diabetic mice showed no enhancement of arginase, VEGF or MCP-1 expression in arginase KO mice. Upregulation of arginase, VEGF and MCP-1 was only observed in the wild-type mice.
The enzymatic uncoupling of eNOS is an important feature of vascular disease states associated with increased oxidative stress and involves upregulation of arginase expression and activity. These findings, showing induction of proinflammatory cytokines by arginase, open a new horizon for therapeutic agents targeting the arginase pathway in the prevention and treatment of retinal and vascular diseases.
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