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Wnt/β-Catenin Signaling Promotes Podocyte Dysfunction and Albuminuria

Chunsun Dai^*, Donna B. Stolz, Lawrence P. Kiss^*, Satdarshan P. Monga^*, Lawrence B. Holzman and Youhua Liu^*

*Department of Pathology and
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan

Correspondence: Dr. Youhua Liu, Department of Pathology, University of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Phone: +1-412-648-8253; Fax: +1-412-648-1916; E-mail: liuy{at}upmc.edu

Received for publication January 7, 2009. Accepted for publication May 13, 2009.

Podocyte dysfunction, one of the major causes of proteinuria, leads to glomerulosclerosis and end stage renal disease, but its underlying mechanism remains poorly understood. Here we show that Wnt/β-catenin signaling plays a critical role in podocyte injury and proteinuria. Treatment with adriamycin induced Wnt and activated β-catenin in mouse podocytes. Overexpression of Wnt1 in vivo activated glomerular β-catenin and aggravated albuminuria and adriamycin-induced suppression of nephrin expression, whereas blockade of Wnt signaling with Dickkopf-1 ameliorated podocyte lesions. Podocyte-specific knockout of β-catenin protected against development of albuminuria after injury. Moreover, pharmacologic activation of β-catenin induced albuminuria in wild-type mice but not in β-catenin-knockout littermates. In human proteinuric kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis, we observed upregulation of Wnt1 and active β-catenin in podocytes. Ectopic expression of either Wnt1 or stabilized β-catenin in vitro induced the transcription factor Snail and suppressed nephrin expression, leading to podocyte dysfunction. These results suggest that targeting hyperactive Wnt/β-catenin signaling may represent a novel therapeutic strategy for proteinuric kidney diseases.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673