Canonical Wnt/Β-catenin signaling mediates transforming growth factor-Β1-driven podocyte injury and proteinuria

Abstract

Transforming growth factor-Β1 (TGF-Β1) 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-Β1 induced Wnt1 expression, Β-catenin activation, and stimulated the expression of Wnt/Β-catenin downstream target genes. Ectopic expression of Wnt1 or Β-catenin mimicked TGF-Β1, induced Snail1, and suppressed nephrin expression. The Wnt antagonist, Dickkopf-1, blocked TGF-Β1-induced Β-catenin activation, Snail1 induction, and nephrin suppression. In vivo, ectopic expression of TGF-Β1 induced Wnt1 expression, activated Β-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 Β-catenin activation, inhibited TGF-Β1-triggered Wnt target gene expression, and mitigated albuminuria. Thus, canonical Wnt/Β-catenin signaling mediates TGF-Β1-driven podocyte injury and proteinuria. These studies suggest that Wnt/Β-catenin signaling may be exploited as a therapeutic target for the treatment of proteinuric kidney diseases. © 2011 International Society of Nephrology.