title: Downregulation of renal tubular Wnt/β-catenin signaling by Dickkopf-3 induces tubular cell death in proteinuric nephropathy.
abstract: Studies on the role of Wnt/β-catenin signaling in different forms of kidney disease have yielded discrepant results. Here, we report the biphasic change of renal β-catenin expression in mice with overload proteinuria in which β-catenin was upregulated at the early stage (4 weeks after disease induction) but abrogated at the late phase (8 weeks). Acute albuminuria was observed at 1 week after bovine serum albumin injection, followed by partial remission at 4 weeks that coincided with overexpression of renal tubular β-catenin. Interestingly, a rebound in albuminuria at 8 weeks was accompanied by downregulated tubular β-catenin expression and heightened tubular apoptosis. In addition, there was an inverse relationship between Dickkopf-3 (Dkk-3) and renal tubular β-catenin expression at these time points. In vitro, a similar trend in β-catenin expression was observed in human kidney-2 (HK-2) cells with acute (upregulation) and prolonged (downregulation) exposure to albumin. Induction of a proapoptotic phenotype by albumin was significantly enhanced by silencing β-catenin in HK-2 cells. Finally, Dkk-3 expression and secretion was increased after prolonged exposure to albumin, leading to the suppression of intracellular β-catenin signaling pathway. The effect of Dkk-3 on β-catenin signaling was confirmed by incubation with exogenous Dkk-3 in HK-2 cells. Taken together, these data suggest that downregulation of tubular β-catenin signaling induced by Dkk-3 has a detrimental role in chronic proteinuria, partially through the increase in apoptosis.
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|The University of Hong Kong Shenzhen Institute of Research and Innovation, China.
authors.forename: D W L
authors.initials: DW
authors.lastname: Wong
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|The University of Hong Kong Shenzhen Institute of Research and Innovation, China.
authors.forename: W H
authors.initials: WH
authors.lastname: Yiu
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|The University of Hong Kong Shenzhen Institute of Research and Innovation, China.
authors.forename: H J
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|The University of Hong Kong Shenzhen Institute of Research and Innovation, China.
authors.forename: R X
authors.initials: RX
authors.lastname: Li
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|The University of Hong Kong Shenzhen Institute of Research and Innovation, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|The University of Hong Kong Shenzhen Institute of Research and Innovation, China.
authors.forename: K W
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: J C K
authors.initials: JC
authors.lastname: Leung
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: L Y Y
authors.initials: LY
authors.lastname: Chan
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: K N
authors.initials: KN
authors.lastname: Lai
authors.affiliation: Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.|The University of Hong Kong Shenzhen Institute of Research and Innovation, China.
authors.forename: S C W
authors.initials: SC
authors.lastname: Tang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D018925:Chemokines; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011507:Proteinuria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; C498624:DKK3 protein, human; C405061:Dkk3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051176:beta Catenin