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Diabetes 51:2241-2248, 2002
© 2002 by the American Diabetes Association, Inc.
Activation of Nuclear Factor-
B Induced by Diabetes and High Glucose Regulates a Proapoptotic Program in Retinal Pericytes
1 Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
2 Department of Medicine, Case Western Reserve University, Cleveland, Ohio
To reconstruct the events that may contribute to the accelerated death of retinal vascular cells in diabetes, we investigated in situ and in vitro the activation of nuclear factor-
B (NF-B), which is triggered by cellular stress and controls several programs of gene expression. The retinal capillaries of diabetic eye donors showed an increased number of pericyte nuclei positive for NF-B, when compared with nondiabetic donors, whereas endothelial cells were negative. Microvascular cell apoptosis and acellular capillaries were increased only in the diabetic donors with numerous NF-B-positive pericytes. Likewise, high glucose in vitro activated NF-B in retinal pericytes but not in endothelial cells, and increased apoptosis only in pericytes. Studies with NF-B inhibitors suggested that in pericytes, basal NF-B has prosurvival functions, whereas NF-B activation induced by high glucose is proapoptotic. Pericytes exposed to high glucose showed increased expression of Bax and of tumor necrosis factor-
, which were prevented by the NF-B inhibitors and mimicked by transfection with the p65 subunit of NF-B, and failed to increase the levels of the NF-B-dependent inhibitors of apoptosis. Colocalization of activated NF-B and Bax overexpression was observed in the retinal pericytes of diabetic donors. A proapoptotic program triggered by NF-B selectively in retinal pericytes in response to hyperglycemia is a possible mechanism for the early demise of pericytes in diabetic retinopathy.
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