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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 2

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Diabetes or AGE-albumin induces transcriptional activity of NF-κB in sci...
Diabetes or AGE-albumin induces transcriptional activity of NF-κB in sciatic nerves. (A) NF-κB–controlled β-globin and β-actin transcription in sciatic nerves of healthy control mice (lanes 1–3) and diabetic mice (lanes 4–7) 6 weeks after induction of diabetes; bar graphs summarize the semiquantitative results (β-globin/β-actin ratio) obtained in all mice studied (black bar, control; gray bar, diabetes). The mean ± SD is reported; *P < 0.05. The number of mice studied was 4 for controls, 5 for diabetes. (B) β-Globin and β-actin transcription in sciatic nerves of diabetic mice with bad glycemic control (lane 1) and good glycemic control due to intensified insulin treatment (lane 2); n = 2 for each group. (C) β-Globin and β-actin transcription in sciatic nerves of healthy controls (lane 1) compared with mice that had had diabetes for 3 months, without (lane 2) and with sRAGE treatment (lane 3); n = 3 for each group. (D and E) β-Globin, NF-κBp65, and β-actin transcription in sciatic nerves of mice treated with native albumin (lane 1), AGE-albumin alone (lane 2), or AGE-albumin in the presence of sRAGE (D, lane 3), anti-RAGE IgG (RAGE-Ab; D, lane 4), or the antioxidant thioctic acid (TA; E, lane 3); n = 3 for each group. (F) IL-6 transcription in sciatic nerves studied in A–E from healthy (lanes 1 and 2) and diabetic (lanes 3–5) mice with bad (lanes 3 and 4) and good (lane 5) glycemic control and mice treated with native albumin (lane 6), AGE-albumin alone (lane 7), or AGE-albumin in the presence of sRAGE (lane 8), anti-RAGE IgG (lane 9), or thioctic acid (lane 10).

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