Wnt/β-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/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.