title: 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.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.forename: Donna B
authors.initials: DB
authors.lastname: Stolz
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Kiss
authors.forename: Satdarshan P
authors.initials: SP
authors.lastname: Monga
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: 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*
chemical_list: 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