Artikel ; Online: TGF-β1-elevated TRPM7 channel regulates collagen expression in hepatic stellate cells via TGF-β1/Smad pathway.
Toxicology and applied pharmacology
2014 Band 280, Heft 2, Seite(n) 335–344
Abstract: ... hepatic stellate cell line). TRPM7 mRNA and protein were measured by Real-time PCR and Western blot in TGF-β1-activated ... production, was decreased in TRPM7 deficient HSC-T6 cells. These observations suggested that TGF-β1 elevates ... TRPM7 expression in HSCs via Smad3-dependant mechanisms, which in turn contributes Smad ...
| Abstract | Transdifferentiation of hepatic stellate cells (HSCs) into myofibroblasts plays a critical role in the development of liver fibrosis, since myofibroblasts are the key cells responsible for excessive deposition of ECM proteins. Transient receptor potential melastatin 7 (TRPM7), a non-selective cation channel with protein serine/threonine kinase activity, has been demonstrated to function in the proliferation of activated HSCs. Here, we investigated the functional role of TRPM7 in collagen deposition in activated HSC-T6 cells (a rat hepatic stellate cell line). TRPM7 mRNA and protein were measured by Real-time PCR and Western blot in TGF-β1-activated HSC-T6 cells in vitro. Results demonstrated that TRPM7 protein was dramatically increased in fibrotic human livers. Stimulation of HSC-T6 cells with TGF-β1 increased TRPM7 mRNA and protein level in a time-dependent manner. Nevertheless, TGF-β1-elicited upregulation of TRPM7 in HSC-T6 cells was abrogated by SB431542 (TGF-β1 receptor blocker) or SIS3 (inhibitor of Smad3 phosphorylation). Additionally, blockade of TRPM7 channels with non-specific TRPM7 blocker 2-APB or synthetic siRNA targeting TRPM7 attenuated TGF-β1-induced expression of myofibroblast markers, as measured by the induction of α-SMA and Col1α1. Silencing TRPM7 also increased the ratio of MMPs/TIMPs by increasing MMP-13 expression and decreasing TIMP-1 and TIMP-2 levels. Strikingly, phosphorylation of p-Smad2 and p-Smad3, associated with collagen production, was decreased in TRPM7 deficient HSC-T6 cells. These observations suggested that TGF-β1 elevates TRPM7 expression in HSCs via Smad3-dependant mechanisms, which in turn contributes Smad protein phosphorylation, and subsequently increases fibrous collagen expression. Therefore, TRPM7 may constitute a useful target for the treatment of liver fibrosis. |
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| Mesh-Begriff(e) | Actins/analysis ; Animals ; Collagen/metabolism ; Collagen Type I/analysis ; Hepatic Stellate Cells/metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Signal Transduction/physiology ; Smad Proteins/physiology ; TRPM Cation Channels/analysis ; TRPM Cation Channels/antagonists & inhibitors ; TRPM Cation Channels/physiology ; Transforming Growth Factor beta1/physiology | |||||
| Chemische Substanzen | Actins ; Collagen Type I ; Smad Proteins ; TRPM Cation Channels ; Transforming Growth Factor beta1 ; collagen type I, alpha 1 chain ; smooth muscle actin, rat ; Collagen (9007-34-5) ; Trpm7 protein, rat (EC 2.7.11.1) | |||||
| Sprache | Englisch | |||||
| Erscheinungsdatum | 2014-10-15 | |||||
| Erscheinungsland | United States | |||||
| Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 204477-8 | |||||
| ISSN | 1096-0333 ; 0041-008X | |||||
| ISSN (online) | 1096-0333 | |||||
| ISSN | 0041-008X | |||||
| DOI | 10.1016/j.taap.2014.08.006 | |||||
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| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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