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Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
,
Renjiao Li,
Bethan Mansfield,
Daniel A. Pass ,
Richard T. Bruce,
Ping Huang,
Rachel Paes de Araújo ,
Bahareh Sadat Haddadi,
Luis A. J. Mur ,
Jordanna Dally ,
Ryan Moseley ,
Rupert Ecker ,
Harry Karmouty-Quintana ,
Keir Lewis ,
A. John Simpson ,
Jeremy P. T. Ward,
Christopher J. Corrigan ,
Renata Z. Jurkowska ,
Benjamin D. Hope-Gill,
Daniela Riccardi ,
Polina L. Yarova
Biomolecules, Volume: 15, Issue: 4, Start page: 509
Swansea University Author:
Keir Lewis
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© 2025 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.
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DOI (Published version): 10.3390/biom15040509
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine–polyamine pathway, play crucial roles in IPF development. Polyamines are agonists...
| Published in: | Biomolecules |
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| ISSN: | 2218-273X |
| Published: |
MDPI AG
2025
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa69250 |
| Abstract: |
Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine–polyamine pathway, play crucial roles in IPF development. Polyamines are agonists of the calcium/cation-sensing receptor (CaSR), activation of which is detrimental for asthma and pulmonary hypertension, but its role in IPF is unknown. To address this question, we evaluated polyamine abundance using metabolomic analysis of IPF patient saliva. Furthermore, we examined CaSR functional expression in human lung fibroblasts (HLFs), assessed the anti-fibrotic effects of a CaSR antagonist, NPS2143, in TGFβ1-activated normal and IPF HLFs by RNA sequencing and immunofluorescence imaging, respectively; and NPS2143 effects on polyamine synthesis in HLFs by immunoassays. Our results demonstrate that polyamine metabolites are increased in IPF patient saliva. Polyamines activate fibroblast CaSR in vitro, elevating intracellular calcium concentration. CaSR inhibition reduced TGFβ1-induced polyamine and pro-fibrotic factor expression in normal and IPF HLFs. TGFβ1 directly stimulated polyamine release by HLFs, an effect that was blocked by NPS2143. This suggests that TGFβ1 promotes CaSR activation through increased polyamine expression, driving a pro-fibrotic response. By halting some polyamine-induced pro-fibrotic changes, CaSR antagonists exhibit disease-modifying potential in IPF onset and development. |
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| Keywords: |
idiopathic pulmonary fibrosis; calcium/cation-sensing receptor; TGFβ1; arginine–polyamine pathway; negative allosteric modulator |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This research was funded by the King’s Commercialisation Institute (grant number: 150902, to D.R.), the Saunders Legacy Lung Research (grant number: 9471 to B.H-G. and D.R.), the Marie Curie ETN “CaSR Biomedicine” (grant number: 675228 to D.R.), the Wellcome Trust (grant number: 221678/Z/20/Z to P.L.Y.], and the Newcastle University Research Excellence Development award (grant number: NU-018860 to P.Y.). L.A.J.M. is partially supported by the Shandong Province “Double-Hundred Talent Plan” Teams (grant number: WSR2023049). The APC was funded by Conselho Nacional de Desenvolvimento Científico e tecnológico—CNPq. |
| Issue: |
4 |
| Start Page: |
509 |