Arginase as a mediator of diabetic retinopathy

Chintan Patel, Modesto Antonio Rojas, Subhadra Priyadarshini Narayanan, Wenbo Zhang, Zhimin Xu, Tahira Lemtalsi, Kanjana Jittiporn, Robert William Caldwell, Ruth B Caldwell

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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 - Sep 16 2013

Fingerprint

Arginase
Diabetic Retinopathy
Retinal Vessels
Retina
Glucose
Nitrites
Vasodilation
Oxidative Stress
Leukostasis
Endothelial Cells
Peroxynitrous Acid
Vascular System Injuries
Gene Deletion
Intercellular Adhesion Molecule-1
Streptozocin
Knockout Mice
Nitrates
Protein Isoforms
Leukocytes
Cell Death

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Patel, C., Rojas, M. A., Narayanan, S. P., Zhang, W., Xu, Z., Lemtalsi, T., ... 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

Arginase as a mediator of diabetic retinopathy. / Patel, Chintan; Rojas, Modesto Antonio; Narayanan, Subhadra Priyadarshini; Zhang, Wenbo; Xu, Zhimin; Lemtalsi, Tahira; Jittiporn, Kanjana; Caldwell, Robert William; Caldwell, Ruth B.

In: Frontiers in Immunology, Vol. 4, No. JUL, Article 173, 16.09.2013.

Research output: Contribution to journalArticle

Patel, C, Rojas, MA, Narayanan, SP, Zhang, W, Xu, Z, Lemtalsi, T, Jittiporn, K, Caldwell, RW & Caldwell, RB 2013, 'Arginase as a mediator of diabetic retinopathy', Frontiers in Immunology, vol. 4, no. JUL, Article 173. https://doi.org/10.3389/fimmu.2013.00173
Patel C, Rojas MA, Narayanan SP, Zhang W, Xu Z, Lemtalsi T et al. Arginase as a mediator of diabetic retinopathy. Frontiers in Immunology. 2013 Sep 16;4(JUL). Article 173. https://doi.org/10.3389/fimmu.2013.00173
Patel, Chintan ; Rojas, Modesto Antonio ; Narayanan, Subhadra Priyadarshini ; Zhang, Wenbo ; Xu, Zhimin ; Lemtalsi, Tahira ; Jittiporn, Kanjana ; Caldwell, Robert William ; Caldwell, Ruth B. / Arginase as a mediator of diabetic retinopathy. In: Frontiers in Immunology. 2013 ; Vol. 4, No. JUL.
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