Diabetes-associated sustained activation of the transcription factor nuclear factor-κB

• Verfasst von: Bierhaus, Angelika [VerfasserIn]
• Verfasst von: Schiekofer, Stephan [VerfasserIn]
• Verfasst von: Schwaninger, Markus [VerfasserIn]
• Verfasst von: Andrassy, Martin [VerfasserIn]
• Verfasst von: Humpert, Per M. [VerfasserIn]
• Verfasst von: Chen, Jiang [VerfasserIn]
• Verfasst von: Hong, Mei [VerfasserIn]
• Verfasst von: Luther, Thomas [VerfasserIn]
• Verfasst von: Henle, Thomas [VerfasserIn]
• Verfasst von: Klöting, Ingrid [VerfasserIn]
• Verfasst von: Morcos, Michael [VerfasserIn]
• Verfasst von: Hofmann, Marion [VerfasserIn]
• Verfasst von: Tritschler, Hans [VerfasserIn]
• Verfasst von: Weigle, Bernd [VerfasserIn]
• Verfasst von: Kasper, Michael [VerfasserIn]
• Verfasst von: Smith, Mark [VerfasserIn]
• Verfasst von: Perry, George [VerfasserIn]
• Verfasst von: Schmidt, Ann-Marie [VerfasserIn]
• Verfasst von: Stern, David M. [VerfasserIn]
• Verfasst von: Häring, Hans-Ulrich [VerfasserIn]
• Verfasst von: Schleicher, Erwin [VerfasserIn]
• Verfasst von: Nawroth, Peter Paul [VerfasserIn]
• Titel: Diabetes-associated sustained activation of the transcription factor nuclear factor-κB
• Verf.angabe: Angelika Bierhaus, Stephan Schiekofer, Markus Schwaninger, Martin Andrassy, Per M. Humpert, Jiang Chen, Mei Hong, Thomas Luther, Thomas Henle, Ingrid Klöting, Michael Morcos, Marion Hofmann, Hans Tritschler, Bernd Weigle, Michael Kasper, Mark Smith, George Perry, Ann-Marie Schmidt, David M. Stern, Hans-Ulrich Häring, Erwin Schleicher, Peter P. Nawroth
• Jahr: 2001
• Umfang: 17 S.
• Fussnoten: Gesehen am 24.03.2022
• Titel Quelle: Enthalten in: Diabetes
• Ort Quelle: Alexandria, Va : Assoc., 1952
• Jahr Quelle: 2001
• Band/Heft Quelle: 50(2001), 12, Seite 2792-2808
• ISSN Quelle: 1939-327X
• DOI: doi:10.2337/diabetes.50.12.2792
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1796592730

Abstract

Activation of the transcription factor nuclear factor-κB (NF-κB) has been suggested to participate in chronic disorders, such as diabetes and its complications. In contrast to the short and transient activation of NF-κB in vitro, we observed a long-lasting sustained activation of NF-κB in the absence of decreased IκBα in mononuclear cells from patients with type 1 diabetes. This was associated with increased transcription of NF-κBp65. A comparable increase in NF-κBp65 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-β peptide (Aβ) to the transmembrane receptor for AGE (RAGE) results in protein synthesis-dependent sustained activation of NF-κB both in vitro and in vivo. Infusion of AGE-albumin into mice bearing a β-globin reporter transgene under control of NF-κB also resulted in prolonged expression of the reporter transgene. In vitro studies showed that RAGE-expressing cells induced sustained translocation of NF-κB (p50/p65) from the cytoplasm into the nucleus for >1 week. Sustained NF-κB activation by ligands of RAGE was mediated by initial degradation of IκB proteins followed by new synthesis of NF-κBp65 mRNA and protein in the presence of newly synthesized IκBα and IκBβ. These data demonstrate that ligands of RAGE can induce sustained activation of NF-κB as a result of increased levels of de novo synthesized NF-κBp65 overriding endogenous negative feedback mechanisms and thus might contribute to the persistent NF-κB activation observed in hyperglycemia and possibly other chronic diseases.