Details

Autor(en) / Beteiligte

• Bierhaus, Angelika
• Haslbeck, Karl-Matthias
• Humpert, Per M
• Liliensiek, Birgit
• Dehmer, Thomas
• Morcos, Michael
• Sayed, Ahmed A R
• Andrassy, Martin
• Schiekofer, Stephan
• Schneider, Jochen G
• Schulz, Jörg B
• Heuss, Dieter
• Neundörfer, Bernhard
• Dierl, Stefan
• Huber, Jochen
• Tritschler, Hans
• Schmidt, Ann-Marie
• Schwaninger, Markus
• Haering, Hans-Ulrich
• Schleicher, Erwin
• Kasper, Michael
• Stern, David M
• Arnold, Bernd
• Nawroth, Peter P

Titel

Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily

Ist Teil von

• The Journal of clinical investigation, 2004-12, Vol.114 (12), p.1741-1751

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2004

Link zum Volltext

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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.