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Carlos Subauste, Jose-Andres C. Portillo, Genevieve Okenka, Timothy S. Kern; CD40 Is Central for Development of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5968.
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CD40 is a member of the TNF receptor superfamily expressed on various cell types. CD40 has been linked to certain inflammatory and neuro-degenerative disorders making CD40 a therapeutic target for these disorders. It is not known if CD40 drives micro-vascular complications of diabetes such as diabetic retinopathy.
: B6 and CD40ko mice were made diabetic by streptozotocin administration. Leukostasis, retinal mRNA levels of TNF-α, ICAM-1, MCP-1, NOS2 and COX-2 and histopathology were examined. Protein levels of these molecules were assessed by flow cytometry, ELISA or immunoblot.
Compared to diabetic B6 mice, diabetic CD40ko mice failed to upregulate ICAM-1, TNF-α, MCP-1, NOS2 and COX-2. These mice also had a marked reduction in retinal leukostasis and did not develop degenerate capillaries. CD40 is expressed on primary human and mouse Muller cells, retinal endothelial cells and microglia. CD40 expression is increased in retinas of diabetic B6 mice. In vitro studies revealed that CD154 (CD40 ligand) upregulated ICAM-1 expression and MCP-1 secretion by human retinal endothelial and Muller cells, as well as NOS2 and COX-2 expression by human Muller cells. CD40 stimulation of Muller cells caused apoptosis of bystander retinal endothelial cells.
These studies provide the first evidence that CD40 is key for the development of diabetic retinopathy.
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