RGD Reference Report - Role of alpha 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy. - Rat Genome Database

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

Authors: Iliaki, E  Poulaki, V  Mitsiades, N  Mitsiades, CS  Miller, JW  Gragoudas, ES 
Citation: Iliaki E, etal., Invest Ophthalmol Vis Sci. 2009 Oct;50(10):4898-904. doi: 10.1167/iovs.08-2013. Epub 2009 Jun 24.
RGD ID: 9698417
Pubmed: PMID:19553613   (View Abstract at PubMed)
DOI: DOI:10.1167/iovs.08-2013   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ITGA4Humandiabetic retinopathy treatmentISOItga4 (Rattus norvegicus)associated with Diabetes Mellitus and ExperimentalRGD 
Itga4Mousediabetic retinopathy treatmentISOItga4 (Rattus norvegicus)associated with Diabetes Mellitus and ExperimentalRGD 
Itga4Ratdiabetic retinopathy treatmentIMP associated with Diabetes Mellitus and ExperimentalRGD 

Objects Annotated

Genes (Rattus norvegicus)
Itga4  (integrin subunit alpha 4)

Genes (Mus musculus)
Itga4  (integrin alpha 4)

Genes (Homo sapiens)
ITGA4  (integrin subunit alpha 4)


Additional Information