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Originally published online as doi:10.2353/ajpath.2008.071070 on April 10, 2008

Published online before print April 10, 2008
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(American Journal of Pathology. 2008;172:1411-1418.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071070

Diabetes-Enhanced Tumor Necrosis Factor-{alpha} Production Promotes Apoptosis and the Loss of Retinal Microvascular Cells in Type 1 and Type 2 Models of Diabetic Retinopathy

Yugal Behl*, Padmaja Krothapalli*, Tesfahun Desta*, Amanda DiPiazza*, Sayon Roy{dagger} and Dana T. Graves*

From the Department of Periodontology and Oral Biology,* School of Dental Medicine, and Departments of Medicine and Ophthalmology,{dagger} School of Medicine, Boston University, Boston, Massachusetts

Retinal microvascular cell loss plays a critical role in the pathogenesis of diabetic retinopathy. To examine this further, type 1 streptozotocin-induced diabetic rats and type 2 Zucker diabetic fatty rats were treated by intravitreal injection of the tumor necrosis factor-specific inhibitor pegsunercept, and the impact was measured by analysis of retinal trypsin digests. For type 2 diabetic rats, the number of endothelial cells and pericytes positive for diabetes-enhanced activated caspase-3 decreased by 81% and 86%, respectively, when treated with pegsunercept (P < 0.05). Similarly, the number of diabetes-enhanced terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive endothelial cells and pericytes decreased by 81% and 67% respectively when treated with pegsunercept (P < 0.05). Diabetes-increased activated caspase-3- and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive microvascular cell numbers were both reduced by 81% and 80%, respectively, in pegsunercept-treated type 1 diabetic rats (P < 0.05). Inhibition of tumor necrosis factor reduced type 1 diabetes-enhanced pericyte ghost formation by 87% and the number of type 2 diabetes-enhanced pericyte ghosts by 62% (P < 0.05). Similarly, increased acellular capillary formation caused by type 1 and type 2 diabetes was reduced by 68% and 67%, respectively, when treated with pegsunercept (P < 0.05). These results demonstrate a previously unrecognized role of tumor necrosis factor-{alpha} in promoting the early pathogenesis of diabetic retinopathy leading to loss of retinal microvascular cells and demonstrate the potential therapeutic benefit of modulating its activity.






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Copyright © 2008 by the American Society for Investigative Pathology.