Arginase as a mediator of diabetic retinopathy

Chintan Patel, Modesto Rojas, S. Priya Narayanan, Wenbo Zhang, Zhimin Xu, Tahira Lemtalsi, Kanjana Jittiporn, R. William Caldwell, Ruth B. Caldwell

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

We have shown previously that diabetes causes increases in retinal arginase activity that are associated with impairment of endothelial cell (EC)-dependent vasodilation and increased formation of the peroxynitrite biomarker nitrotyrosine. Arginase blockade normalizes vasodilation responses and reduces nitrotyrosine formation, suggesting that overactive arginase contributes to diabetic retinopathy by reducing NO and increasing oxidative stress. We tested this hypothesis by studies in streptozotocin-induced diabetic mice and high glucose (HG) treated retinal ECs. Our results show that arginase activity is increased in both diabetic retinas and HGtreated retinal ECs as compared with the controls. Western blot shows that both arginase isoforms are present in retinal vessels and ECs and arginase I is increased in the diabetic vessels and HG-treated retinal ECs. Nitrate/nitrite levels are significantly increased in diabetic retinas, indicating an increase in total NO products. However, levels of nitrite, an indicator of bioavailable NO, are reduced by diabetes. Imaging analysis of NO formation in retinal sections confirmed decreases in NO formation in diabetic retinas. The decrease in NO is accompanied by increased O2.- formation and increased leukocyte attachment in retinal vessels. Studies in knockout mice show that arginase gene deletion enhances NO formation, reduces O2.- and prevents leukostasis in the diabetic retinas. HG treatment of retinal ECs also reduces NO release, increases oxidative stress, increases ICAM-1, and induces EC death. Arginase inhibitor treatment reverses these effects. In conclusion, diabetes- and HG-induced signs of retinal vascular activation and injury are associated with increased arginase activity and expression, decreased bioavailable NO, and increased O2.- formation. Blockade of the arginase pathway prevents these alterations, suggesting a primary role of arginase in the pathophysiological process.

Original languageEnglish (US)
Article numberArticle 173
JournalFrontiers in immunology
Volume4
Issue numberJUL
DOIs
StatePublished - 2013

Keywords

  • Arginase
  • Diabetes
  • Diabetic retinopathy
  • High glucose
  • Nitric oxide
  • Oxidative stress

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Patel, C., Rojas, M., Narayanan, S. P., Zhang, W., Xu, Z., Lemtalsi, T., Jittiporn, K., Caldwell, R. W., & Caldwell, R. B. (2013). Arginase as a mediator of diabetic retinopathy. Frontiers in immunology, 4(JUL), [Article 173]. https://doi.org/10.3389/fimmu.2013.00173