Hyperglycemia-induced Activation of Nuclear Transcription Factor kappaB in Cultured Fibroblasts and Endothelial Cells

Kim, Ki Hun; Kim, Byung Chun; Lee, Kyu Suk

Abstract

BACKGROUND
A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. The transcriptional nuclear factor kappaB(NF-kappaB) can be activated by diverse stimuli such as cytokines, mitogens, oxidative stress, and lipids, leading to the transactivation of several genes that play important roles in the development of atherosclerosis, skin thickness, scleredema adultorum et al. OBJECTIVE AND METHOD: The dysfunction of endothelial cells and fibroblasts plays a role in late diabetic complication. This dysfunction may be caused or exacerbated by expression of many genes potently activated by the NF-kappaB. We have examined whether high glucose conditions to simulate the diabetic state can lead to the activation of NF-kappaB in cultured fibroblasts and endothelial cells RESULT: Within 3h incubation, high glucose (5, 10, 25 mmol/L) alone induced an increase in NF-kappaB activity in endothelial cells and fibroblasts. High glucose also enhanced NF-kappaB activity stimulated by TNF-alpha. Incubation with high glucose for 24h followed by stimulation with TNF-alpha led to a marked potentiation of NF-kappaB activation compared with normoglycemic (5 mmol/L) endothelial cells and fibroblasts exposed to TNF-alpha. An antioxidant thioctic acid and transcription factor decoy for NF-kappaB significantly suppressed the TNF-alpha induced NF-kappaB activity in both endothelial cells and fibroblasts. CONCLUSION: These results suggest that high glucose or high glucose with TNF-alpha cause activation of NF-kappaB. And co-incubation with an antioxidant, thioctic acid, and transcription factor decoy produced the inhibition of glucose-induced NF-kappaB activation. Thus NF-kappaB activation is an early occurence due to the elevations in glucose, which may elicit multiple pathways contributing to the origin of hyperglycemia- or diabetes-induced endothelial and fibroblast cell injury. In summary, our results for the first time suggest that therapeutic strategies involving inhibition of NF-kappaB activation induced by high glucose may help avoid some of the complications of diabetes.