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Role of Smad3 in Platelet-Derived Growth Factor-C induced liver fibrosis.

Authors
 Jung Il Lee  ;  Jocelyn H. Wright  ;  Melissa M. Johnson  ;  Renay L. Bauer  ;  Kristina Sorg  ;  Sebastian Yuen  ;  Brian J. Hayes  ;  Lananh Nguyen  ;  Kimberly J. Riehle  ;  Jean S. Campbell 
Citation
 AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, Vol.310(6) : 436-445, 2016 
Journal Title
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
ISSN
 0363-6143 
Issue Date
2016
MeSH
Animals ; Carcinoma, Hepatocellular/metabolism ; Cell Proliferation/physiology ; Cells, Cultured ; Female ; Hepatic Stellate Cells/metabolism ; Hepatocytes/metabolism ; Liver/physiology ; Liver Cirrhosis/metabolism* ; Liver Neoplasms/metabolism ; Lymphokines/metabolism* ; Male ; Mice ; Mice, Knockout ; Mice, Transgenic ; Platelet-Derived Growth Factor/metabolism* ; Rats ; Signal Transduction/physiology ; Smad3 Protein/metabolism* ; Transforming Growth Factor beta/metabolism
Keywords
PDGF ; Smad ; TGFβ ; hepatic stellate cells ; liver fibrosis
Abstract
Chronic liver injury leads to fibrosis and cirrhosis. Cirrhosis, the end stage of chronic liver disease, is a leading cause of death worldwide and increases the risk of developing hepatocellular carcinoma. Currently, there is a lack of effective antifibrotic therapies to treat fibrosis and cirrhosis. Development of antifibrotic therapies requires an in-depth understanding of the cellular and molecular mechanisms involved in inflammation and fibrosis after hepatic injury. Two growth factor signaling pathways that regulate liver fibrosis are transforming growth factor-β (TGFβ) and platelet-derived growth factor (PDGF). However, their specific contributions to fibrogenesis are not well understood. Using a genetic model of liver fibrosis, we investigated whether the canonical TGFβ signaling pathway was necessary for fibrogenesis. PDGF-C transgenic (PDGF-C Tg) mice were intercrossed with mice that lack Smad3, and molecular and histological fibrosis was analyzed. PDGF-C Tg mice that also lacked Smad3 had less fibrosis and improved liver lobule architecture. Loss of Smad3 also reduced expression of collagen genes, which were induced by PDGF-C, but not the expression of genes frequently associated with hepatic stellate cell (HSC) activation. In vitro HSCs isolated from Smad3-null mice proliferated more slowly than cells from wild-type mice. Taken together, these findings indicate that PDGF-C activates TGFβ/Smad3 signaling pathways to regulate HSC proliferation, collagen production and ultimately fibrosis. In summary, these results suggest that inhibition of both PDGF and TGFβ signaling pathways may be required to effectively attenuate fibrogenesis in patients with chronic liver disease.
Full Text
http://ajpcell.physiology.org/content/310/6/C436
DOI
10.1152/ajpcell.00423.2014
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Lee, Jung Il(이정일) ORCID logo https://orcid.org/0000-0002-0142-1398
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146423
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