ABSTRACT
Many potential causes for painful diabetic neuropathy have been proposed including actions of cytokines and growth factors. High mobility group protein B1 (HMGB1) is a RAGE (also known as AGER) agonist whose levels are increased in diabetes and that contributes to pain by modulating peripheral inflammatory responses. HMGB1 enhances nociceptive behaviour in naïve animals through an unknown mechanism. We tested the hypothesis that HMGB1 causes pain through direct neuronal activation of RAGE and alteration of nociceptive neuronal responsiveness. HMGB1 and RAGE expression were increased in skin and primary sensory (dorsal root ganglion, DRG) neurons of diabetic rats at times when pain behaviour was enhanced. Agonist-evoked TRPV1-mediated Ca2+ responses increased in cultured DRG neurons from diabetic rats and in neurons from naïve rats exposed to high glucose concentrations. HMGB1-mediated increases in TRPV1-evoked Ca2+ responses in DRG neurons were RAGE- and PKC-dependent, and this was blocked by co-administration of the growth factor splice variant VEGF-A165b. Pain behaviour and the DRG RAGE expression increases were blocked by VEGF-A165b treatment of diabetic rats in vivo. Hence, we conclude that HMGB1–RAGE activation sensitises DRG neurons in vitro, and that VEGF-A165b blocks HMGB-1–RAGE DRG activation, which may contribute to its analgesic properties in vivo.
Footnotes
Competing interests
L.F.D. and D.O.B. are co-inventors on patents protecting alternative RNA splicing control and VEGF-A splice variants for therapeutic application in a number of different conditions. L.F.D. and D.O.B. are founder equity holders in, and consultants (both) and director (D.O.B.) to Exonate Ltd, a University of Nottingham spin-out company with a focus on development of alternative RNA splicing control for therapeutic application in a number of different conditions, including analgesia and neuroprotection (www.exonate.com). Exonate made no financial contribution to this study. The University of Nottingham also holds equity in Exonate Ltd.
Author contributions
Conceptualization: S.M.B., R.P.H., Z.B., M.S., N.V., N.B., D.O.B., L.F.D.; Methodology: S.M.B., R.P.H., Z.B., N.B., D.O.B., L.F.D.; Formal analysis: S.M.B., L.F.D.; Investigation: S.M.B., R.P.H., Z.B., M.S., N.V., K.P., N.B.; Resources: R.P.H., D.O.B., L.F.D.; Writing - original draft: S.M.B., L.F.D.; Writing - review & editing: S.M.B., R.P.H., Z.B., M.S., N.V., N.B., D.O.B., L.F.D.; Supervision: R.P.H., D.O.B., L.F.D.; Project administration: S.M.B., R.P.H., D.O.B., L.F.D.; Funding acquisition: R.P.H., D.O.B., L.F.D.
Funding
This work was supported by the Medical Research Council [grant number MR/K020366/1] and Arthritis Research UK [grant number 20400]; the MCR grant to D.O.B., Arthritis Research UK grant to L.F.D., R.P.H. and D.O.B. This work was also supported by funding from the University of Nottingham (S.M.B., R.P.H., D.O.B., L.F.D.), Diabetes UK (11/0004192 to L.F.D., and 10/0004152 to D.O.B.) and the European Foundation for the Study of Diabetes Microvascular Programme supported by Novartis (to R.P.H.). Deposited in PMC for immediate release.
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.215939.supplemental
- Received February 21, 2018.
- Accepted June 14, 2018.
- © 2018. Published by The Company of Biologists Ltd
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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