title: Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily.
abstract: 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.
authors.affiliation: University of Heidelberg, Department of Medicine I, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. angelika_bierhaus@med.uni-heidelberg.de
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Karl-Matthias
authors.initials: KM
authors.lastname: Haslbeck
authors.forename: Per M
authors.initials: PM
authors.lastname: Humpert
authors.forename: Birgit
authors.initials: B
authors.lastname: Liliensiek
authors.forename: Thomas
authors.initials: T
authors.lastname: Dehmer
authors.forename: Michael
authors.initials: M
authors.lastname: Morcos
authors.forename: Ahmed A R
authors.initials: AA
authors.lastname: Sayed
authors.forename: Martin
authors.initials: M
authors.lastname: Andrassy
authors.forename: Stephan
authors.initials: S
authors.lastname: Schiekofer
authors.forename: Jochen G
authors.initials: JG
authors.lastname: Schneider
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Dieter
authors.initials: D
authors.lastname: Heuss
authors.forename: Bernhard
authors.initials: B
authors.lastname: Neundörfer
authors.forename: Stefan
authors.initials: S
authors.lastname: Dierl
authors.forename: Jochen
authors.initials: J
authors.lastname: Huber
authors.forename: Hans
authors.initials: H
authors.lastname: Tritschler
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Schmidt
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Haering
authors.forename: Erwin
authors.initials: E
authors.lastname: Schleicher
authors.forename: Michael
authors.initials: M
authors.lastname: Kasper
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: 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
chemical_list: 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