title: Pro-fibrogenic potential of PDGF-D in liver fibrosis.
abstract: OBJECTIVE
  We analyzed the expression of platelet-derived growth factor D (PDGF-D) in an experimental bile duct-ligated (BDL) rat model and assessed its biological function in cultured hepatic stellate cells (HSC) and myofibroblasts (MFB).
  
  
  METHODS
  The mRNA for PDGF-A, -B, -C, -D and for PDGF receptor-alpha and -beta chains (PDGFRalpha and PDGFRbeta) in normal and fibrotic rat livers was assessed quantitatively. Protein levels of PDGF-D were quantified by immunoblotting and immunohistochemistry.
  
  
  RESULTS
  The relative mRNA expression of all PDGF isoforms and receptors upregulated upon BDL and PDGF-A, -B and -D expression was significantly higher than that of PDGF-C. PDGF-D and PDGFRbeta protein also increased markedly. Immunostaining revealed that PDGF-D is localized along the fibrotic septa of the periportal- and perisinusoidal areas. Besides PDGF-B, PDGF-D is the second most potent PDGF isoform in PDGFRbeta signaling within HSC/MFB, evidenced by PDGFRbeta autophosphorylation and activation of the downstream signaling molecules ERK1/2-, JNK-, p38 MAPK, and PKB/Akt while PDGF-C effects were minimal. PDGF-D exerted mitogenic and fibrogenic effects in both cultured HSC and MFB comparable to PDGF-B but PDGF-A and -C showed only marginal fibrogenic effects.
  
  
  CONCLUSIONS
  PDGF-D possesses potential pathogenetic properties for HSC activation and matrix remodeling in liver fibrosis.
authors.affiliation: Institute of Clinical Chemistry and Pathobiochemistry, and Division of Nephrology, RWTH-University Hospital Aachen, D-52074 Aachen, Germany.
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.forename: Claudia R C
authors.initials: CR
authors.lastname: van Roeyen
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Axel M
authors.initials: AM
authors.lastname: Gressner
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003600:Cytosol / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000473:pathology*; D008222:Lymphokines / Q000378:metabolism / Q000502:physiology*; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D017931:DNA Primers; D008024:Ligands; D008222:Lymphokines; C498952:Pdgfd protein, rat; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger