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

Angelika Bierhaus, Karl Matthias Haslbeck, Per M. Humpert, Birgit Liliensiek, Thomas Dehmer, Michael Morcos, Ahmed A.R. Sayed, Martin Andrassy, Stephan Schiekofer, Jochen G. Schneider, Jörg B. Schulz, Dieter Heuss, Bernhard Neundörfer, Stefan Dierl, Jochen Huber, Hans Tritschler, Ann Marie Schmidt, Markus Schwaninger, Hans Ulrich Haering, Erwin Schleicher & 4 others Michael Kasper, David Stern, Bernd Arnold, Peter P. Nawroth

Research output: Contribution to journalArticle

220 Citations (Scopus)

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-κB 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-κBp65, and IL-6 colocalized in the microvasculature of patients with diabetic neuropathy. Activation of NF-κB and NF-κB-dependent gene expression was upregulated in peripheral nerves of diabetic mice, induced by advanced glycation end products, and prevented by RAGE blockade. NF-κB 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-κB axis operates in diabetic neuropathy, by mediating functional sensory deficits, and that its inhibition may provide new therapeutic approaches.

Original languageEnglish (US)
Pages (from-to)1741-1751
Number of pages11
JournalJournal of Clinical Investigation
Volume114
Issue number12
DOIs
StatePublished - Jan 1 2004

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Pain Perception
Diabetic Neuropathies
Immunoglobulins
Sural Nerve
Advanced Glycosylation End Products
Microvessels
Peripheral Nerves
Nerve Fibers
Interleukin-6
Advanced Glycosylation End Product-Specific Receptor
Ligands
Biopsy
Gene Expression

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Bierhaus, A., Haslbeck, K. M., Humpert, P. M., Liliensiek, B., Dehmer, T., Morcos, M., ... Nawroth, P. P. (2004). Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. Journal of Clinical Investigation, 114(12), 1741-1751. https://doi.org/10.1172/JCI18058

Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. / 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; Arnold, Bernd; Nawroth, Peter P.

In: Journal of Clinical Investigation, Vol. 114, No. 12, 01.01.2004, p. 1741-1751.

Research output: Contribution to journalArticle

Bierhaus, A, Haslbeck, KM, Humpert, PM, Liliensiek, B, Dehmer, T, Morcos, M, Sayed, AAR, Andrassy, M, Schiekofer, S, Schneider, JG, Schulz, JB, Heuss, D, Neundörfer, B, Dierl, S, Huber, J, Tritschler, H, Schmidt, AM, Schwaninger, M, Haering, HU, Schleicher, E, Kasper, M, Stern, D, Arnold, B & Nawroth, PP 2004, 'Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily', Journal of Clinical Investigation, vol. 114, no. 12, pp. 1741-1751. https://doi.org/10.1172/JCI18058
Bierhaus A, Haslbeck KM, Humpert PM, Liliensiek B, Dehmer T, Morcos M et al. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. Journal of Clinical Investigation. 2004 Jan 1;114(12):1741-1751. https://doi.org/10.1172/JCI18058
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 ; Arnold, Bernd ; Nawroth, Peter P. / Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. In: Journal of Clinical Investigation. 2004 ; Vol. 114, No. 12. pp. 1741-1751.
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