RGD Reference Report - Dominant-negative soluble PDGF-beta receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis. - Rat Genome Database

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Dominant-negative soluble PDGF-beta receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis.

Authors: Borkham-Kamphorst, E  Herrmann, J  Stoll, D  Treptau, J  Gressner, AM  Weiskirchen, R 
Citation: Borkham-Kamphorst E, etal., Lab Invest. 2004 Jun;84(6):766-77.
RGD ID: 2292206
Pubmed: PMID:15077122   (View Abstract at PubMed)
DOI: DOI:10.1038/labinvest.3700094   (Journal Full-text)

Hepatic fibrogenesis is a consequence of hepatic stellate cells that become activated and transdifferentiate into a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. In this process, platelet-derived growth factor (PDGF) is the most potent stimulus for hepatic stellate cell proliferation and migration, and is overexpressed during active hepatic fibrogenesis. This cytokine binds to the PDGF receptor type beta, activates Ras and sequentially propagates the stimulatory signal sequentially via phosphorylation of Raf-1, MEK and the extracellular-signal regulated kinases ERK1/ERK2. Hepatic injury is associated with both increased autocrine PDGF signaling and upregulation of PDGF receptor. In this study, we report that a dominant-negative soluble PDGF-beta receptor consisting of a chimeric IgG containing the extracellular portion of the PDGF receptor type beta blocks HSC activation and attenuates fibrogenesis induced by ligation of the common bile duct in rats. In culture-activated hepatic stellate cells, the soluble receptor blocks phosphorylation of endogenous PDGF receptor, phosphorylation of the ERK1/EKR2 signal and reduces proliferative activities of HSC. In vivo, both the delivery of the purified soluble PDGF antagonist and the administration of adenoviruses expressing the artificial transgene were able to reduce significantly the expression of collagen and alpha-smooth muscle actin. Our results demonstrate that PDGF plays a critical role in the progression and initiation of experimental liver fibrogenesis, and suggest that early anti-PDGF intervention should have a therapeutical impact on the treatment of liver fibrogenesis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Experimental Liver Cirrhosis  ISOPdgfrb (Rattus norvegicus)2292206; 2292206 RGD 
Experimental Liver Cirrhosis  IMP 2292206 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pdgfrb  (platelet derived growth factor receptor beta)

Genes (Mus musculus)
Pdgfrb  (platelet derived growth factor receptor, beta polypeptide)

Genes (Homo sapiens)
PDGFRB  (platelet derived growth factor receptor beta)


Additional Information