Diabetes-associated sustained activation of the transcription factor nuclear factor-kappaB.
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.
Bierhaus
A
A
Department of Medicine I and Department of Neurology, University of Heidelberg, Heidelberg, Germany.
Schiekofer
S
S
Schwaninger
M
M
Andrassy
M
M
Humpert
P M
PM
Chen
J
J
Hong
M
M
Luther
T
T
Henle
T
T
Klöting
I
I
Morcos
M
M
Hofmann
M
M
Tritschler
H
H
Weigle
B
B
Kasper
M
M
Smith
M
M
Perry
G
G
Schmidt
A M
AM
Stern
D M
DM
Häring
H U
HU
Schleicher
E
E
Nawroth
P P
PP
D000328:Adult; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005246:Feedback; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D051996:Transcription Factor RelA
D016229:Amyloid beta-Peptides; D017127:Glycation End Products, Advanced; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D051996:Transcription Factor RelA; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D004247:DNA