期刊
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
卷 26, 期 3, 页码 677-691出版社
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2013101067
关键词
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资金
- National Basic Research Program of China [2012CB517700]
- National Science Foundation of China [81130011, 81370014]
- National Institutes of Health [DK064005, DK091239]
- American Heart Association [13FTF16990086]
Activation of beta-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 beta-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 beta-catenin. This change in WT1 / beta-catenin ratio was accompanied by loss of podocyte-specific nephrin, podocalyxin, and synaptopodin and acquisition of mesenchynnal markers Snail1, alpha-smooth muscle actin, and fibroblast-specific protein 1. In vitro, overexpression of beta-catenin induced WT1 protein degradation through the ubiquitin proteasomal pathway, which was blocked by MG-132. WT1 and beta-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 beta-catenin by Wnt3a repressed WT1 and its target gene expression. In vivo, blockade of Wnt/beta-catenin signaling by endogenous antagonist Klotho induced WT1 and restored podocyte integrity in adriamycin nephropathy. These results show that beta-catenin specifically targets WT1 for ubiquitin-mediated degradation, leading to podocyte dedifferentiation and mesenchymal transition. Our data also suggest that WT1 and beta-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.
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