Biomolecules, Vol. 15, Pages 509: Calcium-Sensing Receptor as a Novel Target for the Treatment of Idiopathic Pulmonary Fibrosis
Biomolecules doi: 10.3390/biom15040509
Authors:
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 E. Lewis
A. John Simpson
Jeremy P. T. Ward
Christopher J. Corrigan
Renata Z. Jurkowska
Benjamin D. Hope-Gill
Daniela Riccardi
Polina L. Yarova
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.
Source link
Kasope Wolffs www.mdpi.com
