title: Platelet-derived growth factor (PDGF)-C neutralization reveals differential roles of PDGF receptors in liver and kidney fibrosis.
abstract: Platelet-derived growth factors (PDGF) are key mediators of organ fibrosis. We investigated whether PDGF-C(-/-) mice or mice treated with neutralizing PDGF-C antibodies are protected from bile duct ligation-induced liver fibrosis, and we compared the effects with those of PDGF-C deficiency or neutralization on kidney fibrosis induced by unilateral ureteral obstruction. Unexpectedly, and in contrast to kidney fibrosis, PDGF-C deficiency or antagonism did not protect from liver fibrosis or functional liver impairment. Furthermore, the hepatic infiltration of monocytes/macrophages/dendritic cells and chemokine mRNA expression (CC chemokine ligand [CCL]5, CCL2, and CC chemokine receptor 2 [CCR2]) remained unchanged. Transcript expression of PDGF ligands increased in both liver and kidney fibrosis and was not affected by neutralization of PDGF-C. In kidney fibrosis, PDGF-C deficiency or antagonism led to reduced expression and signaling of PDGF-receptor (R)-α- and PDGFR-β-chains. In contrast, in liver fibrosis there was either no difference (PDGF-C(-/-) mice) or even an upregulation of PDGFR-β and signaling (anti-PDGF-C group). Finally, in vitro studies in portal myofibroblasts pointed to a predominant role of PDGF-B and PDGF-D signaling in liver fibrosis. In conclusion, our study revealed significant differences between kidney and liver fibrosis in that PDGF-C mediates kidney fibrosis, whereas antagonism of PDGF-C in liver fibrosis appears to be counteracted by significant upregulation and increased PDGFR-β signaling. PDGF-C antagonism, therefore, may not be effective to treat liver fibrosis.
authors.affiliation: Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
authors.forename: Ina V
authors.initials: IV
authors.lastname: Martin
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zok
authors.forename: Claudia R C
authors.initials: CR
authors.lastname: van Roeyen
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.forename: Kanishka
authors.initials: K
authors.lastname: Hittatiya
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Fischer
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Frank
authors.initials: F
authors.lastname: Eitner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.forename: Tammo
authors.initials: T
authors.lastname: Ostendorf
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C; D017479:Receptors, Platelet-Derived Growth Factor