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- Title
Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.
- Authors
Bierhaus, A; Schiekofer, S; Schwaninger, M; Andrassy, M; Humpert, P M; Chen, J; Hong, M; Luther, T; Henle, T; Klöting, I; Morcos, M; Hofmann, M; Tritschler, H; Weigle, B; Kasper, M; Smith, M; Perry, G; Schmidt, A M; Stern, D M; Häring, H U; Schleicher, E; Nawroth, P P
- Abstract
Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-kappaB in vitro, we observed a long-lasting sustained activation of NF-kappaB in the absence of decreased IkappaBalpha in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-kappaBp65. A comparable increase in NF-kappaBp65 antigen and mRNA was also observed in vascular endothelial cells of diabetic rats. As a mechanism, we propose that binding of ligands such as advanced glycosylation end products (AGEs), members of the S100 family, or amyloid-beta peptide (Abeta) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-kappaB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a beta-globin reporter transgene under control of NF-kappaB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-kappaB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-kappaB activation by ligands of RAGE was mediated by initial degradation of IkappaB proteins followed by new synthesis of NF-kappaBp65 mRNA and protein in the presence of newly synthesized IkappaBalpha and IkappaBbeta. These data demonstrate that ligands of RAGE can induce sustained activation of NF-kappaB as a result of increased levels of de novo synthesized NF-kappaBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-kappaB activation observed in hyperglycemia and possibly other chronic diseases.
- Publication
Diabetes, 2001, Vol 50, Issue 12, p2792
- ISSN
0012-1797
- Publication type
Journal Article
- DOI
10.2337/diabetes.50.12.2792