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.
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.
Behl
Yugal
Y
Department of Periodontology and Oral Biology, Boston University School of Dental Medicine, Boston, MA 02118, USA.
Krothapalli
Padmaja
P
Desta
Tesfahun
T
DiPiazza
Amanda
A
Roy
Sayon
S
Graves
Dana T
DT
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D008833:Microcirculation / Q000473:pathology; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012171:Retinal Vessels / Q000378:metabolism* / Q000473:pathology; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D053148:Caspase 3