title: Activation of nuclear factor-kappaB induced by diabetes and high glucose regulates a proapoptotic program in retinal pericytes.
abstract: 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-kappaB (NF-kappaB), 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-kappaB, 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-kappaB-positive pericytes. Likewise, high glucose in vitro activated NF-kappaB in retinal pericytes but not in endothelial cells, and increased apoptosis only in pericytes. Studies with NF-kappaB inhibitors suggested that in pericytes, basal NF-kappaB has prosurvival functions, whereas NF-kappaB activation induced by high glucose is proapoptotic. Pericytes exposed to high glucose showed increased expression of Bax and of tumor necrosis factor-alpha, which were prevented by the NF-kappaB inhibitors and mimicked by transfection with the p65 subunit of NF-kappaB, and failed to increase the levels of the NF-kappaB-dependent inhibitors of apoptosis. Colocalization of activated NF-kappaB and Bax overexpression was observed in the retinal pericytes of diabetic donors. A proapoptotic program triggered by NF-kappaB selectively in retinal pericytes in response to hyperglycemia is a possible mechanism for the early demise of pericytes in diabetic retinopathy.
authors.affiliation: Schepens Eye Research Institute, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Romeo
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Liu
authors.forename: Veronica
authors.initials: V
authors.lastname: Asnaghi
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: Mara
authors.initials: M
authors.lastname: Lorenzi
mesh_terms: D000368:Aged; D017209:Apoptosis; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D002423:Cause of Death; D021983:Cyclophilins / Q000235:genetics; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D008297:Male; D008833:Microcirculation / Q000502:physiology*; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D020286:Pericytes / Q000166:cytology* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D012016:Reference Values; D012160:Retina / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels / Q000473:pathology / Q000502:physiology / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D021983:Cyclophilins