Gadolinium-promoted precipitation of calcium phosphate is associated with profibrotic activation of RAW 264.7 macrophages

Gadolinium-based contrast agents are now being linked to nephrogenic systemic fibrosis (NSF). The exact mechanism by which gadolinium species act in the pathogenesis of NSF is not fully understood. In this study, we evaluated the effect of gadolinium chloride (GdCl3) on the precipitation of calcium phosphate, and examined the role of the gadolinium-containing precipitates in the profibrotic activation of macrophages. In a free-drift system, the induction time was markedly reduced with increasing concentration of GdCl3, accompanied by alterations of morphology and composition of the precipitates. In complete cell culture medium, the addition of GdCl3 resulted in formation of particles around 200-300 nm. In an in vitro cellular model with RAW 264.7 macrophages, GdCl3 increased the production of TGF-beta 1 and IL-6 via the activation of PKC and ERK signaling pathway. Our findings demonstrate that GdCl3 promotes calcium phosphate precipitation and induces profibrotic activation of macrophages. (C) 2010 Elsevier Ltd. All rights reserved.