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Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily
Angelika Bierhaus, … , Bernd Arnold, Peter P. Nawroth
Angelika Bierhaus, … , Bernd Arnold, Peter P. Nawroth
Published December 15, 2004
Citation Information: J Clin Invest. 2004;114(12):1741-1751. https://doi.org/10.1172/JCI18058.
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Article Metabolism

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

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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.

Authors

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, Michael Kasper, David M. Stern, Bernd Arnold, Peter P. Nawroth

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Figure 1

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Localization of CML, RAGE, activated NF-κBp65, and IL-6 antigens in sura...
Localization of CML, RAGE, activated NF-κBp65, and IL-6 antigens in sural nerve biopsies from patients with diabetes mellitus. (A) Representative immunohistochemical staining of a sural nerve biopsy from a 51-year-old female patient with type 1 diabetes mellitus: CML (first column), RAGE (second column), activated NF-κBp65 (third column), and IL-6 antigen (fourth column) in epineurial vessels (top), perineurium (middle), and endoneurial vessels (bottom). Positivity for the respective antigen is indicated by intense red staining. The faint blue background color is due to counterstaining with hemalaun, indicating the integrity of the tissue investigated. Scale bars: 100 μm. (B) Quantification of staining intensities of epineurial vessels (EP), perineurium (P), and endoneurial vessels (EN) in nondiabetic (black bars, n = 8) and diabetic (gray bars, n = 10) patients. Data are means ± SD; single asterisks denote P values less than 0.05, which we considered to be statistically significant; double asterisks denote P values less than 0.005, which we considered to be highly statistically significant. (C) Comparison of the staining intensity for the RAGE ligand CML (left) and the RAGE ligand S100A8/A9 (right) in sural nerve biopsies from a 56-year-old male patient with CMT-I (top) and a 66-year-old male patient with type 2 diabetes (bottom). Representative epineurial vessels are shown. Magnification, ×400.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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