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TRPM7 restrains plasmin activity and promotes transforming growth factor-β1 signaling in primary human lung fibroblasts.
Arch. Toxicol. 96, 2767-2783 (2022)
Publ. Version/Full Text
Research data
DOI
PMC
Sustained exposure of the lung to various environmental or occupational toxins may eventually lead to pulmonary fibrosis, a devastating disease with no cure. Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins such as fibronectin and collagens. The peptidase plasmin degrades the ECM, but protein levels of the plasmin activator inhibitor-1 (PAI-1) are increased in fibrotic lung tissue, thereby dampening plasmin activity. Transforming growth factor-β1 (TGF-β1)-induced activation of SMAD transcription factors promotes ECM deposition by enhancing collagen, fibronectin and PAI-1 levels in pulmonary fibroblasts. Hence, counteracting TGF-β1-induced signaling is a promising approach for the therapy of pulmonary fibrosis. Transient receptor potential cation channel subfamily M Member 7 (TRPM7) supports TGF-β1-promoted SMAD signaling in T-lymphocytes and the progression of fibrosis in kidney and heart. Thus, we investigated possible effects of TRPM7 on plasmin activity, ECM levels and TGF-β1 signaling in primary human pulmonary fibroblasts (pHPF). We found that two structurally unrelated TRPM7 blockers enhanced plasmin activity and reduced fibronectin or PAI-1 protein levels in pHPF under basal conditions. Further, TRPM7 blockade strongly inhibited fibronectin and collagen deposition induced by sustained TGF-β1 stimulation. In line with these data, inhibition of TRPM7 activity diminished TGF-β1-triggered phosphorylation of SMAD-2, SMAD-3/4-dependent reporter activation and PAI-1 mRNA levels. Overall, we uncover TRPM7 as a novel supporter of TGF-β1 signaling in pHPF and propose TRPM7 blockers as new candidates to control excessive ECM levels under pathophysiological conditions conducive to pulmonary fibrosis.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Plasmin ; Primary Human Lung Fibroblasts ; Pulmonary Fibrosis ; Tgf-β1 ; Trpm7
ISSN (print) / ISBN
0340-5761
e-ISSN
1432-0738
Journal
Archives of Toxicology
Quellenangaben
Volume: 96,
Issue: 10,
Pages: 2767-2783
Publisher
Springer
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Lung Health and Immunity (LHI)
Grants
NIGMS NIH HHS
Deutsche Forschungsgemeinschaft
Deutsche Forschungsgemeinschaft