Pro-fibrogenic potential of PDGF-D in liver fibrosis.
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.
Borkham-Kamphorst
Erawan
E
Institute of Clinical Chemistry and Pathobiochemistry, and Division of Nephrology, RWTH-University Hospital Aachen, D-52074 Aachen, Germany.
van Roeyen
Claudia R C
CR
Ostendorf
Tammo
T
Floege
Jürgen
J
Gressner
Axel M
AM
Weiskirchen
Ralf
R
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
D017931:DNA Primers; D008024:Ligands; D008222:Lymphokines; C498952:Pdgfd protein, rat; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger