Higham, James P;
Bhebhe, Charity N;
Gupta, Rohit A;
Tranter, Michael M;
Barakat, Farah M;
Dogra, Harween;
Bab, Natalie;
... Bulmer, David C; + view all
(2024)
Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease.
Pain
10.1097/j.pain.0000000000003159.
(In press).
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Abstract
Visceral pain is a leading cause of morbidity in inflammatory bowel disease (IBD), contributing significantly to reduced quality of life. Currently available analgesics often lack efficacy or have intolerable side effects, driving the need for a more complete understanding of the mechanisms causing pain. Whole transcriptome gene expression analysis was performed by bulk RNA sequencing of colonic biopsies from patients with ulcerative colitis (UC) and Crohn disease (CD) reporting abdominal pain and compared with noninflamed control biopsies. Putative pronociceptive mediators were identified based on analysis of differentially expressed genes in IBD biopsy tissue and single-cell gene expression in murine colonic sensory neurons. Pronociceptive activity of identified mediators was assessed in assays of sensory neuron and colonic afferent activity. RNA sequencing analysis highlighted a 7.6-fold increase in the expression of angiotensinogen transcripts, Agt, which encode the precursor to angiotensin II (Ang II), in samples from UC patients (P = 3.2 × 10-8). Consistent with the marked expression of the angiotensin AT1 receptor in colonic sensory neurons, Ang II elicited an increase in intracellular Ca2+ in capsaicin-sensitive, voltage-gated sodium channel subtype NaV1.8-positive sensory neurons. Ang II also evoked action potential discharge in high-threshold colonic nociceptors. These effects were inhibited by the AT1 receptor antagonist valsartan. Findings from our study identify AT1 receptor-mediated colonic nociceptor activation as a novel pathway of visceral nociception in patients with UC. This work highlights the potential utility of angiotensin receptor blockers, such as valsartan, as treatments for pain in IBD.
| Type: | Article |
|---|---|
| Title: | Transcriptomic profiling reveals a pronociceptive role for angiotensin II in inflammatory bowel disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1097/j.pain.0000000000003159 |
| Publisher version: | http://dx.doi.org/10.1097/j.pain.0000000000003159 |
| Language: | English |
| Additional information: | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| Keywords: | Visceral pain, Inflammatory bowel disease, Colitis, Angiotensin II, AT1 receptors, Nociception, Angiotensin receptor blocker |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10186826 |
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