Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A.
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Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A. / Thieringer, Florian; Maass, Thorsten; Czochra, Piotr; Klopcic, Borut; Conrad, Ilka; Friebe, Diana; Schirmacher, Peter; Lohse, Ansgar W.; Blessing, Manfred; Galle, Peter R; Teufel, Andreas; Kanzler, Stephan.
in: GENE, Jahrgang 423, Nr. 1, 1, 2008, S. 23-28.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A.
AU - Thieringer, Florian
AU - Maass, Thorsten
AU - Czochra, Piotr
AU - Klopcic, Borut
AU - Conrad, Ilka
AU - Friebe, Diana
AU - Schirmacher, Peter
AU - Lohse, Ansgar W.
AU - Blessing, Manfred
AU - Galle, Peter R
AU - Teufel, Andreas
AU - Kanzler, Stephan
PY - 2008
Y1 - 2008
N2 - Platelet derived growth factor (PDGF) plays a central role in repair mechanisms after acute and chronic tissue damage. To further evaluate the role of PDGF-A in liver fibrogenesis in vivo, we generated transgenic mice with hepatocyte-specific overexpression of PDGF-A using the CRP-gene promoter. Transgenic but not wildtype mice showed expression of PDGF-A mRNA in the liver. Hepatic PDGF-A overexpression was accompanied by a significant increase in hepatic procollagen III mRNA expression as well as TGF-beta1 expression. Liver histology showed increased deposition of extracellular matrix in transgenic but not in wildtype mice. PDGF-A-transgenic mice showed positive sinusoidal staining for alpha-SMA indicating an activation of hepatic stellate cells. Since the profibrogenic effect of PDGF-A was accompanied by increased TGF-beta1 protein concentration in the liver of transgenic mice, it can be postulated that PDGF-A upregulates expression of TGF-beta1 which is a strong activator of hepatic stellate cells. Thus, these results point towards a fibrosis induction by PDGF-A via the TGF-beta1 signalling pathway. In conclusion, expression and functional analysis of PDGF-A in the liver of transgenic mice suggest a relevant profibrogenic role of PDGF-A via TGF-beta1 induction. Counteracting PDGF-A may therefore be one of the effects of tyrosine kinase inhibitors which showed protective effects in animal models of liver fibrosis.
AB - Platelet derived growth factor (PDGF) plays a central role in repair mechanisms after acute and chronic tissue damage. To further evaluate the role of PDGF-A in liver fibrogenesis in vivo, we generated transgenic mice with hepatocyte-specific overexpression of PDGF-A using the CRP-gene promoter. Transgenic but not wildtype mice showed expression of PDGF-A mRNA in the liver. Hepatic PDGF-A overexpression was accompanied by a significant increase in hepatic procollagen III mRNA expression as well as TGF-beta1 expression. Liver histology showed increased deposition of extracellular matrix in transgenic but not in wildtype mice. PDGF-A-transgenic mice showed positive sinusoidal staining for alpha-SMA indicating an activation of hepatic stellate cells. Since the profibrogenic effect of PDGF-A was accompanied by increased TGF-beta1 protein concentration in the liver of transgenic mice, it can be postulated that PDGF-A upregulates expression of TGF-beta1 which is a strong activator of hepatic stellate cells. Thus, these results point towards a fibrosis induction by PDGF-A via the TGF-beta1 signalling pathway. In conclusion, expression and functional analysis of PDGF-A in the liver of transgenic mice suggest a relevant profibrogenic role of PDGF-A via TGF-beta1 induction. Counteracting PDGF-A may therefore be one of the effects of tyrosine kinase inhibitors which showed protective effects in animal models of liver fibrosis.
M3 - SCORING: Zeitschriftenaufsatz
VL - 423
SP - 23
EP - 28
JO - GENE
JF - GENE
SN - 0378-1119
IS - 1
M1 - 1
ER -
