Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis

Wolffs, Kasope; Li, Renjiao; Mansfield, Bethan; Pass, Daniel A.; Bruce, Richard T.; Huang, Ping; de, Rachel Paes; Haddadi, Bahareh Sadat; J., Luis A.; Dally, Jordanna; Moseley, Ryan; Ecker, Rupert; Karmouty-Quintana, Harry; Lewis, Keir; Simpson, A. John; T., Jeremy P.; Corrigan, Christopher J.; Jurkowska, Renata Z.; Hope-Gill, Benjamin D.; Riccardi, Daniela; Yarova, Polina L.

doi:10.3390/biom15040509

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Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis

Kasope Wolffs

, 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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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...

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Published in:	Biomolecules
ISSN:	2218-273X
Published:	MDPI AG 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa69250

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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. 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spelling	2025-04-10T11:19:19.7196573 v2 69250 2025-04-10 Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis bc53c343c975d6e0ad88c1d8b9ddd70c 0000-0002-8248-6774 Keir Lewis Keir Lewis true false 2025-04-10 MEDS 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. Journal Article Biomolecules 15 4 509 MDPI AG 2218-273X idiopathic pulmonary fibrosis; calcium/cation-sensing receptor; TGFβ1; arginine–polyamine pathway; negative allosteric modulator 1 4 2025 2025-04-01 10.3390/biom15040509 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee 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. 2025-04-10T11:19:19.7196573 2025-04-10T11:10:34.9986537 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Kasope Wolffs 0009-0001-9838-5396 1 Renjiao Li 2 Bethan Mansfield 3 Daniel A. Pass 0000-0003-2799-8432 4 Richard T. Bruce 5 Ping Huang 6 Rachel Paes de Araújo 0000-0003-0712-8739 7 Bahareh Sadat Haddadi 8 Luis A. J. Mur 0000-0002-0961-9817 9 Jordanna Dally 0000-0002-2221-2683 10 Ryan Moseley 0000-0002-2812-6735 11 Rupert Ecker 0000-0002-1095-8592 12 Harry Karmouty-Quintana 0000-0003-4753-9823 13 Keir Lewis 0000-0002-8248-6774 14 A. John Simpson 0000-0003-4731-7294 15 Jeremy P. T. Ward 16 Christopher J. Corrigan 0000-0002-0706-6534 17 Renata Z. Jurkowska 0000-0002-4507-2222 18 Benjamin D. Hope-Gill 19 Daniela Riccardi 0000-0002-7322-3163 20 Polina L. Yarova 0000-0002-7534-7995 21 69250__33981__49707ff2d2ac42349861c75c34e32b5a.pdf 69250.VOR.pdf 2025-04-10T11:16:49.3593090 Output 4093989 application/pdf Version of Record true © 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. true eng https://creativecommons.org/licenses/by/4.0/
title	Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
spellingShingle	Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis Keir Lewis
title_short	Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
title_full	Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
title_fullStr	Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
title_full_unstemmed	Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
title_sort	Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
author_id_str_mv	bc53c343c975d6e0ad88c1d8b9ddd70c
author_id_fullname_str_mv	bc53c343c975d6e0ad88c1d8b9ddd70c_***_Keir Lewis
author	Keir Lewis
author2	Kasope Wolffs 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
format	Journal article
container_title	Biomolecules
container_volume	15
container_issue	4
container_start_page	509
publishDate	2025
institution	Swansea University
issn	2218-273X
doi_str_mv	10.3390/biom15040509
publisher	MDPI AG
college_str	Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description	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.
published_date	2025-04-01T12:40:47Z
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Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis

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