Canonical Wnt/β-catenin signaling mediates transforming growth factor-β1-driven podocyte injury and proteinuria

Transforming growth factor-beta 1 (TGF-beta 1) upregulation occurs in virtually all chronic kidney diseases and is associated with podocyte injury and proteinuria; however, the mechanisms contributing to this in vivo are ambiguous. In vitro, incubation of podocytes with TGF-beta 1 induced Wnt1 expression, beta-catenin activation, and stimulated the expression of Wnt/beta-catenin downstream target genes. Ectopic expression of Wnt1 or beta-catenin mimicked TGF-beta 1, induced Snail1, and suppressed nephrin expression. The Wnt antagonist, Dickkopf-1, blocked TGF-beta 1-induced beta-catenin activation, Snail1 induction, and nephrin suppression. In vivo, ectopic expression of TGF-beta 1 induced Wnt1 expression, activated beta-catenin, and upregulated Wnt target genes such as Snail1, MMP-7, MMP-9, desmin, Fsp1, and PAI-1 in mouse glomeruli, leading to podocyte injury and albuminuria. Consistently, concomitant expression of Dickkopf-1 gene abolished beta-catenin activation, inhibited TGF-beta 1-triggered Wnt target gene expression, and mitigated albuminuria. Thus, canonical Wnt/beta-catenin signaling mediates TGF-beta 1-driven podocyte injury and proteinuria. These studies suggest that Wnt/beta-catenin signaling may be exploited as a therapeutic target for the treatment of proteinuric kidney diseases. Kidney International (2011) 80, 1159-1169; doi:10.1038/ki.2011.255; published online 10 August 2011