배양한 섬유아세포와 혈관내피세포에서 고혈당과 TNF-α에의한 NF-κB 의 활성화

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 kB(NF-kB) 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 at. 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-kB. We have examined whether high glucose conditions to simulate the diabetic state can lead to the activation of NF-kB in cultured fibroblasts and endothelial cells Result : Within ３h incubation, high glucose (５, １０, ２５ mmol/L) alone induced an increase in NF-kB activity in endothelial cells and fibroblasts. High glucose also enhanced NF-kB activity stimulated by TNF-a. Incubation with high glucose for ２４h followed by stimulation with TNF-a led to a marked potentiation of NF-kB activation compared with normoglycemic (５ mmol/L) endothelial cells and fibroblasts exposed to TNF-a. An antioxidant thioctic acid and transcription factor decoy for NF-kB significantly suppressed the TNF-n induced NF-kB activity in both endothelial cells and fib-roblasts. Conclusion : These results suggest that high glucose or high glucose with TNF-n cause activation of NF-KB. And co-incubation with an antioxidant, thioctic acid, and transcription factor decoy produced the inhibition of glucose-induced NF-KB activation. Thus NF-KB activation is an early occurrence 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-kB activation induced by high glucose nay help avoid some of the complications of diabetes.