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      Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.

      Diabetes
      Adult, Amyloid beta-Peptides, metabolism, pharmacology, Animals, Cell Nucleus, Cytoplasm, DNA, Diabetes Mellitus, Type 1, Endothelium, Vascular, Feedback, Female, Glycosylation End Products, Advanced, Humans, I-kappa B Proteins, Immunohistochemistry, Leukocytes, Mononuclear, Male, Mice, Mice, Transgenic, Middle Aged, NF-kappa B, analysis, genetics, physiology, RNA, Messenger, biosynthesis, Rats, Rats, Sprague-Dawley, Receptors, Immunologic, S100 Proteins, Serum Albumin, Bovine, Transcription Factor RelA

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          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.

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