title: Classical transient receptor potential 6 (TRPC6) channels support myofibroblast differentiation and development of experimental pulmonary fibrosis.
abstract: Pulmonary fibrosis (PF) is a chronic progressive lung disease without effective medical treatment options leading to respiratory failure and death within 3-5years of diagnosis. The pathological process of PF is driven by aberrant wound-healing involving fibroblasts and myofibroblasts differentiated by secreted profibrotic transforming growth factor β (TGF-β1). Classical transient receptor potential 6 (TRPC6), a Na+- and Ca2+-permeable cation channel, is able to promote myofibroblast conversion of primary rat cardiac and human dermal fibroblasts and TRPC6-deficiency impaired wound healing after injury. To study a potential role of TRPC6 in the development of PF we analyzed lung function, gene and protein expression in wild-type (WT) and TRPC6-deficient (TRPC6-/-) lungs utilizing a bleomycin-induced PF-model. Fibrotic WT-mice showed a significant higher death rate while bleomycin-treated TRPC6-deficient mice were partly protected from fibrosis as a consequence of a lower production of collagen and an almost normal function of the respiratory system (reduced resistance and elastance compared to fibrotic WT-mice). On a molecular level TGF-β1 induced TRPC6 up-regulation, increased Ca2+influx and nuclear NFAT localization in WT primary murine lung fibroblasts (PMLFs) resulting in higher stress fiber formation and accelerated contraction rates as compared to treated TRPC6-deficient fibroblasts. Therefore, we conclude that TRPC6 is an important determinant for TGF-β1-induced myofibroblast differentiation during fibrosis and specific channel inhibitors might be beneficial in a future treatment of PF.
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hofmann
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fiedler
authors.affiliation: Research Unit Lung Repair and Regeneration, Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vierkotten
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Weber
authors.affiliation: Research Unit Lung Repair and Regeneration, Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Klee
authors.affiliation: Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease, Member of the German Center for Lung Research (DZL), Helmholtz Zentrum, Munich, Germany.
authors.forename: Jie
authors.initials: J
authors.lastname: Jia
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zwickenpflug
authors.affiliation: Experimental and Clinical Pharmacology and Toxicology, Saarland University, Homburg, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Storch
authors.affiliation: Comprehensive Pneumology Center (CPC), Institute of Lung Biology and Disease, Member of the German Center for Lung Research (DZL), Helmholtz Zentrum, Munich, Germany.
authors.forename: Ali Önder
authors.initials: AÖ
authors.lastname: Yildirim
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.affiliation: Research Unit Lung Repair and Regeneration, Comprehensive Pneumology Center, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Königshoff
authors.affiliation: Walther-Straub-Institute of Pharmacology and Toxicology, Member of the German Center for Lung Research (DZL), University of Munich, Munich, Germany. Electronic address: Alexander.Dietrich@lrz.uni-muenchen.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D000074287:TRPC6 Cation Channel; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D053773:Transforming Growth Factor beta1; C492146:Trpc6 protein, mouse
keywords: Cell contraction; Myofibroblast differentiation; Primary murine lung fibroblasts; Pulmonary fibrosis; TGF-β1; TRPC6