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: Ina V Martin, Erawan Borkham-Kamphorst, Stephanie Zok, Claudia R C van Roeyen, Ulf Eriksson, Peter Boor, Kanishka Hittatiya, Hans-Peter Fischer, Hermann E Wasmuth, Ralf Weiskirchen, Frank Eitner, Jürgen Floege, Tammo Ostendorf
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 1 Pg. 107-17 (Jan 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23141925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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