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Y. Behl, S. Roy, T. Desta, S. Roy, D.T. Graves; TNF– Alpha Inhibition Reduces Diabetes Induced Pro–Apoptotic Retinal Gene Expression . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1727.
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To test the hypothesis that TNF dysregulation in the diabetic retina drives proapoptotic gene expression.
Sprague Dawley rats were randomly assigned to Control, Diabetic and Diabetic + TNF inhibitor groups (n=6). Diabetes was induced by streptozotocin & confirmed by blood glucose measurements. After four weeks of diabetes, animals were injected intravitreally with first dose of Pegsunercept, (PEG sTNFRI; A TNF–specific inhibitor, 50 µg), followed by a second dose three weeks later. Three weeks after second injection the animals were euthanized and eyes were enucleated and retinas isolated. Total RNA was isolated and subjected to Focused Microarray and data mining was done using GEArray Expression Analysis Suite. Selective gene expression results were validated by real time qPCR.
Diabetes induced a two fold increase in mRNA level of 8 out of 11 proapoptotic genes and a two fold decrease in 5 out of 13 antiapoptotic genes and in addition it stimulated a two fold increase in mRNA levels of 57 out of 72 genes that are involved in inflammation and endothelial cell activity. TNF inhibition substantially reduced mRNA levels of 7 out of 11 pro–apoptotic genes. These results suggested that the gene expression pattern of retinal tissues in diabetic rats can be associated with increased apoptosis, resulting in a significant increase in cell death. It showed that the TNF inhibition of apoptotic genes may play a role in the reduced cell death associated with diabetic retinopathy and may offer a potential treatment with TNF inhibitor.
TNF represents a significant mechanism by which diabetes leads to altered levels of gene expressions that regulate inflammation, apoptosis and endothelial cell function in the retina.
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