Role of alpha 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy.

Abstract

PURPOSE:

The pathophysiology of diabetic retinopathy is mediated by leukocyte adhesion to the vascular endothelium of the diabetic retina, which results in endothelial injury, blood-retina barrier breakdown, and capillary nonperfusion. Leukocyte adhesion is triggered by the interaction of vascular endothelium adhesion molecules, such as ICAM-1, with leukocyte integrins, such as CD18. Inhibition of ICAM-1/CD18 signaling suppresses but does not completely abolish the cardinal manifestations of diabetic retinopathy, suggesting a role for additional adhesion molecules. Integrin alpha 4 (CD49d), in complex with integrin beta1, forms very late antigen-4 (VLA-4), which interacts with vascular cell adhesion molecule-1. The authors have now studied the role of integrin alpha 4/CD49d in the pathogenesis of diabetic retinopathy.

METHODS:

Diabetes mellitus was induced in Long Evans rats with streptozotocin, and an anti-alpha 4 integrin/CD49d neutralizing antibody was injected 5 and 10 days later. Two weeks after streptozotocin administration, vascular leakage was quantified with the Evans Blue technique. Leukostasis was measured with a static adhesion assay ex vivo and the FITC-lectin perfusion method in vivo. Retinal VEGF and TNF-alpha levels and NF-kappaB activity were measured by ELISA.

RESULTS:

Blockade of alpha 4 integrin/CD49d attenuated the diabetes-induced upregulation of NF-kappaB activation, VEGF, and TNF-alpha protein levels and reduced significantly diabetes-induced leukocyte adhesion and vascular leakage.

CONCLUSIONS:

These data identify alpha 4 integrin/CD49d as a mediator of leukocyte adhesion and the resultant early signature abnormalities of diabetic retinopathy. Inhibition of this signaling pathway may hold promise for clinical activity in patients with diabetes.

• Authors: Eirini Iliaki, Vassiliki Poulaki, Nicholas Mitsiades, Constantine S Mitsiades, Joan W Miller, Evangelos S Gragoudas
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 50 Issue 10 Pg. 4898-904 (Oct 2009) ISSN: 1552-5783 [Electronic] United States
• PMID: 19553613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, rat
• Integrin alpha4

Topics

• Animals
• Antibodies, Blocking
• Blood-Retinal Barrier
• Capillary Permeability
• Cell Adhesion
• Diabetes Mellitus, Experimental (etiology, metabolism)
• Diabetic Retinopathy (etiology, metabolism)
• Endothelium, Vascular (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Integrin alpha4 (physiology)
• Leukocytes (physiology)
• Leukostasis (etiology, metabolism)
• Male
• NF-kappa B (metabolism)
• Rats
• Rats, Long-Evans
• Retinal Vessels (cytology)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation
• Vascular Endothelial Growth Factor A (metabolism)