Platelet-derived Growth Factor (PDGF)-C Neutralization Reveals Differential Roles of PDGF Receptors in Liver and Kidney Fibrosis

Am J Pathol. 2013 Jan;182(1):107-17. doi: 10.1016/j.ajpath.2012.09.006. Epub 2012 Nov 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Fibrosis
  • Kidney / pathology*
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / prevention & control
  • Lymphokines / antagonists & inhibitors
  • Lymphokines / deficiency
  • Lymphokines / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myofibroblasts / metabolism
  • Platelet-Derived Growth Factor / antagonists & inhibitors
  • Platelet-Derived Growth Factor / deficiency
  • Platelet-Derived Growth Factor / physiology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Platelet-Derived Growth Factor / metabolism
  • Receptors, Platelet-Derived Growth Factor / physiology*
  • Signal Transduction / physiology
  • Up-Regulation / physiology
  • Ureteral Obstruction / complications

Substances

  • Lymphokines
  • Platelet-Derived Growth Factor
  • platelet-derived growth factor C
  • Receptors, Platelet-Derived Growth Factor