Downregulation of renal tubular Wnt/β-catenin signaling by Dickkopf-3 induces tubular cell death in proteinuric nephropathy

D. W.L. Wong, W. H. Yiu, H. J. Wu, R. X. Li, Y. Liu, K. W. Chan, J. C.K. Leung, L. Y.Y. Chan, K. N. Lai, S. C.W. Tang

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6 Scopus citations

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.

Original languageEnglish
Article numbere2155
JournalCell Death and Disease
Volume7
Issue number3
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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    Wong, D. W. L., Yiu, W. H., Wu, H. J., Li, R. X., Liu, Y., Chan, K. W., Leung, J. C. K., Chan, L. Y. Y., Lai, K. N., & Tang, S. C. W. (2016). Downregulation of renal tubular Wnt/β-catenin signaling by Dickkopf-3 induces tubular cell death in proteinuric nephropathy. Cell Death and Disease, 7(3), [e2155]. https://doi.org/10.1038/cddis.2016.62