title: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.|Center for Kidney Disease, Second Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D007674:Kidney Diseases / Q000209:etiology; D051379:Mice; D050199:Podocytes / Q000473:pathology*; D011507:Proteinuria / Q000209:etiology*; D015398:Signal Transduction / Q000502:physiology; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D053773:Transforming Growth Factor beta1; D051153:Wnt Proteins; D051176:beta Catenin