Wnt/beta-Catenin-Promoted Macrophage Alternative Activation Contributes to Kidney Fibrosis

The Wnt/beta-catenin pathway is crucial in normal development and throughout life, but aberrant activation of this pathway has been linked to kidney fibrosis, although the mechanisms involved remain incompletely determined. Here, we investigated the role ofWnt/beta-catenin in regulatingmacrophage activation and the contribution thereof to kidney fibrosis. Treatment of macrophages with Wnt3a exacerbated IL-4- or TGF beta 1-induced macrophage alternative (M2) polarization and the phosphorylation and nuclear translocation of STAT3 in vitro. Conversely, inhibition of Wnt/beta-catenin signaling prevented these IL-4- or TGF beta 1-induced processes. In a mouse model, induced deletion of beta-catenin in macrophages attenuated the fibrosis, macrophage accumulation, and M2 polarization observed in the kidneys of wild-type littermates after unilateral ureter obstruction. This study shows that activation of Wnt/beta-catenin signaling promotes kidney fibrosis by stimulating macrophage M2 polarization.