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- Title
Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.
- Authors
Bierhaus, Angelika; Schiekofer, Stephan; Schwaninger, Markus; Andrassy, Martin; Humpert, Per M.; Chen, Jiang; Hong, Mei; Luther, Thomas; Henle, Thomas; Klöting, Ingrid; Morcos, Michael; Hofmann, Marion; Tritschler, Hans; Weigle, Bernd; Kasper, Michael; Smith, Mark; Perry, George; Schmidt, Ann-Marie; Stern, David M.; Haring, Hans-Ulrich
- 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.
- Subjects
NF-kappa B; DIABETES complications
- Publication
Diabetes, 2001, Vol 50, Issue 12, p2792
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.50.12.2792