Wnt/beta-catenin signaling promotes podocyte dysfunction and albuminuria.
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.
Dai
Chunsun
C
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Stolz
Donna B
DB
Kiss
Lawrence P
LP
Monga
Satdarshan P
SP
Holzman
Lawrence B
LB
Liu
Youhua
Y
D000419:Albuminuria / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001706:Biopsy; D002461:Cell Line, Transformed; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D051155:Wnt1 Protein / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D008565:Membrane Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C495247:WNT1 protein, human; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D051176:beta Catenin; C113267:nephrin