Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily.
Molecular events that result in loss of pain perception are poorly understood in diabetic neuropathy. Our results show that the receptor for advanced glycation end products (RAGE), a receptor associated with sustained NF-kappaB activation in the diabetic microenvironment, has a central role in sensory neuronal dysfunction. In sural nerve biopsies, ligands of RAGE, the receptor itself, activated NF-kappaBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-kappaB and NF-kappaB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-kappaB activation was blunted in RAGE-null (RAGE(-/-)) mice compared with robust enhancement in strain-matched controls, even 6 months after diabetes induction. Loss of pain perception, indicative of long-standing diabetic neuropathy, was reversed in WT mice treated with soluble RAGE. Most importantly, loss of pain perception was largely prevented in RAGE(-/-) mice, although they were not protected from diabetes-induced loss of PGP9.5-positive plantar nerve fibers. These data demonstrate, for the first time to our knowledge, that the RAGE-NF-kappaB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.
Bierhaus
Angelika
A
University of Heidelberg, Department of Medicine I, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. angelika_bierhaus@med.uni-heidelberg.de
Haslbeck
Karl-Matthias
KM
Humpert
Per M
PM
Liliensiek
Birgit
B
Dehmer
Thomas
T
Morcos
Michael
M
Sayed
Ahmed A R
AA
Andrassy
Martin
M
Schiekofer
Stephan
S
Schneider
Jochen G
JG
Schulz
Jörg B
JB
Heuss
Dieter
D
Neundörfer
Bernhard
B
Dierl
Stefan
S
Huber
Jochen
J
Tritschler
Hans
H
Schmidt
Ann-Marie
AM
Schwaninger
Markus
M
Haering
Hans-Ulrich
HU
Schleicher
Erwin
E
Kasper
Michael
M
Stern
David M
DM
Arnold
Bernd
B
Nawroth
Peter P
PP
D000818:Animals; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D005914:Globins / Q000378:metabolism; D017127:Glycation End Products, Advanced; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010146:Pain; D017288:Pain Threshold; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D013997:Time Factors; D051996:Transcription Factor RelA; D015854:Up-Regulation
D001786:Blood Glucose; D017127:Glycation End Products, Advanced; D007136:Immunoglobulins; D015850:Interleukin-6; D008024:Ligands; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D051996:Transcription Factor RelA; D005914:Globins