Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury

Modesto Rojas, Wenbo Zhang, Zhimin Xu, Tahira Lemtalsi, Phillip Chandler, Haroldo A. Toque, Robert W. Caldwell, Ruth B. Caldwell

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Objective: Diabetic retinopathy, a major cause of blindness, is characterized by increased expression of vascular endothelial growth factor (VEGF), leukocyte attachment to the vessel walls and increased vascular permeability. Previous work has shown that reactive oxygen species (ROS) produced by the superoxide generating enzyme NOX2/NADPH oxidase play a crucial role in the vascular pathology. The aim of this work was to identify the cellular sources of the damaging NOX2 activity by studies using bone marrow chimera mice. Methods: Bone marrow cells were collected from the femurs and tibias of wild type and NOX2 deficient (NOX2-/-) donor mice and injected intravenously into lethally irradiated NOX2-/- and wild type recipients. Following recovery from radiation, mice were rendered diabetic by streptozotocin injections. The following groups of bone marrow chimeras were studied: non-diabetic WT→WT, diabetic WT→WT, diabetic WT→NOX2-/-, diabetic NOX2-/-→WT. After 4 weeks of diabetes, early signs of retinopathy were examined by measuring ROS, expression of VEGF and ICAM-1, leukocyte attachment to the vessel wall and vascular permeability. Results: The retinas of the diabetic WT→WT chimeras showed significant increases in ROS as compared with the non-diabetic chimeras. These diabetes-induced alterations were correlated with increases in expression of VEGF and ICAM-1, leukocyte adhesion and vascular permeability. Each of these diabetes-induced alterations were significantly attenuated in the diabetic WT→NOX2-/- and NOX2-/-→WT chimera groups (p<0.05). Conclusion: NOX2-generated ROS produced by both bone marrow-derived cells and resident retinal cells contribute importantly to retinal vascular injury in the diabetic retina. Targeting NOX2 in bone marrow and/or retinal cells may represent a novel therapeutic strategy for the treatment/prevention of vascular injury in the diabetic retina.

Original languageEnglish (US)
Article numbere84357
JournalPLoS One
Volume8
Issue number12
DOIs
StatePublished - Dec 17 2013

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Retinal Vessels
Vascular System Injuries
Medical problems
retina
blood vessels
chimerism
bone marrow
diabetes
Retina
Bone
Bone Marrow
Reactive Oxygen Species
Capillary Permeability
vascular endothelial growth factors
reactive oxygen species
Vascular Endothelial Growth Factor A
Leukocytes
Cells
Intercellular Adhesion Molecule-1
leukocytes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury. / Rojas, Modesto; Zhang, Wenbo; Xu, Zhimin; Lemtalsi, Tahira; Chandler, Phillip; Toque, Haroldo A.; Caldwell, Robert W.; Caldwell, Ruth B.

In: PLoS One, Vol. 8, No. 12, e84357, 17.12.2013.

Research output: Contribution to journalArticle

Rojas, M, Zhang, W, Xu, Z, Lemtalsi, T, Chandler, P, Toque, HA, Caldwell, RW & Caldwell, RB 2013, 'Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury', PLoS One, vol. 8, no. 12, e84357. https://doi.org/10.1371/journal.pone.0084357
Rojas, Modesto ; Zhang, Wenbo ; Xu, Zhimin ; Lemtalsi, Tahira ; Chandler, Phillip ; Toque, Haroldo A. ; Caldwell, Robert W. ; Caldwell, Ruth B. / Requirement of NOX2 expression in both retina and bone marrow for diabetes-induced retinal vascular injury. In: PLoS One. 2013 ; Vol. 8, No. 12.
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AU - Toque, Haroldo A.

AU - Caldwell, Robert W.

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AB - Objective: Diabetic retinopathy, a major cause of blindness, is characterized by increased expression of vascular endothelial growth factor (VEGF), leukocyte attachment to the vessel walls and increased vascular permeability. Previous work has shown that reactive oxygen species (ROS) produced by the superoxide generating enzyme NOX2/NADPH oxidase play a crucial role in the vascular pathology. The aim of this work was to identify the cellular sources of the damaging NOX2 activity by studies using bone marrow chimera mice. Methods: Bone marrow cells were collected from the femurs and tibias of wild type and NOX2 deficient (NOX2-/-) donor mice and injected intravenously into lethally irradiated NOX2-/- and wild type recipients. Following recovery from radiation, mice were rendered diabetic by streptozotocin injections. The following groups of bone marrow chimeras were studied: non-diabetic WT→WT, diabetic WT→WT, diabetic WT→NOX2-/-, diabetic NOX2-/-→WT. After 4 weeks of diabetes, early signs of retinopathy were examined by measuring ROS, expression of VEGF and ICAM-1, leukocyte attachment to the vessel wall and vascular permeability. Results: The retinas of the diabetic WT→WT chimeras showed significant increases in ROS as compared with the non-diabetic chimeras. These diabetes-induced alterations were correlated with increases in expression of VEGF and ICAM-1, leukocyte adhesion and vascular permeability. Each of these diabetes-induced alterations were significantly attenuated in the diabetic WT→NOX2-/- and NOX2-/-→WT chimera groups (p<0.05). Conclusion: NOX2-generated ROS produced by both bone marrow-derived cells and resident retinal cells contribute importantly to retinal vascular injury in the diabetic retina. Targeting NOX2 in bone marrow and/or retinal cells may represent a novel therapeutic strategy for the treatment/prevention of vascular injury in the diabetic retina.

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