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Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria.


ABSTRACT: 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/beta-catenin signaling plays a critical role in podocyte injury and proteinuria. Treatment with adriamycin induced Wnt and activated beta-catenin in mouse podocytes. Overexpression of Wnt1 in vivo activated glomerular beta-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 beta-catenin protected against development of albuminuria after injury. Moreover, pharmacologic activation of beta-catenin induced albuminuria in wild-type mice but not in beta-catenin-knockout littermates. In human proteinuric kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis, we observed upregulation of Wnt1 and active beta-catenin in podocytes. Ectopic expression of either Wnt1 or stabilized beta-catenin in vitro induced the transcription factor Snail and suppressed nephrin expression, leading to podocyte dysfunction. These results suggest that targeting hyperactive Wnt/beta-catenin signaling may represent a novel therapeutic strategy for proteinuric kidney diseases.

SUBMITTER: Dai C 

PROVIDER: S-EPMC2736766 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria.

Dai Chunsun C   Stolz Donna B DB   Kiss Lawrence P LP   Monga Satdarshan P SP   Holzman Lawrence B LB   Liu Youhua Y  

Journal of the American Society of Nephrology : JASN 20090723 9


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/beta-catenin signaling plays a critical role in podocyte injury and proteinuria. Treatment with adriamycin induced Wnt and activated beta-catenin in mouse podocytes. Overexpression of Wnt1 in vivo activated glomerular beta-catenin and aggravated albuminuria and adriamycin-induced suppression of nephrin  ...[more]

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