title: Mutual antagonism of Wilms' tumor 1 and β-catenin dictates podocyte health and disease.
abstract: Activation of β-catenin, the intracellular mediator of canonical Wnt signaling, has a critical role in mediating podocyte injury and proteinuria. However, the underlying mechanisms remain poorly understood. Here, we show that β-catenin triggers ubiquitin-mediated protein degradation of Wilms' tumor 1 (WT1) and functionally antagonizes its action. In mice injected with adriamycin, WT1 protein was progressively lost in glomerular podocytes at 1, 3, and 5 weeks after injection. Notably, loss of WT1 apparently did not result from podocyte depletion but was closely associated with upregulation of β-catenin. This change in WT1/β-catenin ratio was accompanied by loss of podocyte-specific nephrin, podocalyxin, and synaptopodin and acquisition of mesenchymal markers Snail1, α-smooth muscle actin, and fibroblast-specific protein 1. In vitro, overexpression of β-catenin induced WT1 protein degradation through the ubiquitin proteasomal pathway, which was blocked by MG-132. WT1 and β-catenin also competed for binding to common transcriptional coactivator CREB-binding protein and mutually repressed the expression of their respective target genes. In glomerular miniorgan culture, activation of β-catenin by Wnt3a repressed WT1 and its target gene expression. In vivo, blockade of Wnt/β-catenin signaling by endogenous antagonist Klotho induced WT1 and restored podocyte integrity in adriamycin nephropathy. These results show that β-catenin specifically targets WT1 for ubiquitin-mediated degradation, leading to podocyte dedifferentiation and mesenchymal transition. Our data also suggest that WT1 and β-catenin have opposing roles in podocyte biology, and that the ratio of their expression levels dictates the state of podocyte health and disease in vivo.
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and Department of Pathology and.
authors: Lili
authors: L
authors: Zhou
authors: Department of Pathology and.
authors: Yingjian
authors: Y
authors: Li
authors: Department of Pathology and.
authors: Weichun
authors: W
authors: He
authors: Department of Pathology and.
authors: Dong
authors: D
authors: Zhou
authors: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors: Roderick J
authors: RJ
authors: Tan
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors: Jing
authors: J
authors: Nie
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors: Fan Fan
authors: FF
authors: Hou
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and Department of Pathology and liuy@upmc.edu.
authors: Youhua
authors: Y
authors: Liu
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D002460:Cell Line; D004317:Doxorubicin; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000378:metabolism; D050199:Podocytes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D025721:WT1 Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D008565:Membrane Proteins; C498709:Pag1 protein, mouse; D010750:Phosphoproteins; D025801:Ubiquitin; D025721:WT1 Proteins; D051176:beta Catenin; D004317:Doxorubicin; D046988:Proteasome Endopeptidase Complex
keywords: WT1; glomerular disease; podocyte; proteinuria; β-catenin