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J Am Soc Nephrol. 2015 Mar;26(3):677-91. doi: 10.1681/ASN.2013101067. Epub 2014 Jul 28.

Mutual antagonism of Wilms' tumor 1 and β-catenin dictates podocyte health and disease.

Author information

1
State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and Department of Pathology and.
2
Department of Pathology and.
3
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
4
State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
5
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.

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.

KEYWORDS:

WT1; glomerular disease; podocyte; proteinuria; β-catenin

PMID:
25071087
PMCID:
PMC4341470
DOI:
10.1681/ASN.2013101067
[Indexed for MEDLINE]
Free PMC Article

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