Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A.
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.
Thieringer
Florian
F
1st Department of Medicine, Johannes-Gutenberg-University, Mainz, Germany.
Maass
Thorsten
T
Czochra
Piotr
P
Klopcic
Borut
B
Conrad
Ilka
I
Friebe
Diana
D
Schirmacher
Peter
P
Lohse
Ansgar W
AW
Blessing
Manfred
M
Galle
Peter R
PR
Teufel
Andreas
A
Kanzler
Stephan
S
D000818:Animals; D002097:C-Reactive Protein / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D024061:Collagen Type III; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C075278:platelet-derived growth factor A; D002097:C-Reactive Protein