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

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)-alpha- and PDGFR-beta-chains. In contrast, in liver fibrosis there was either no difference (PDGF-C-/- mice) or even an upregulation of PDGFR-beta 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-beta signaling. PDGF-C antagonism, therefore, may not be effective to treat liver fibrosis. (Am J Pathol 2013, 182: 107-117; http://dx.doi.org/10.1016/j.ajpath.2012.09.006)