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/beta-catenin signaling in different forms of kidney disease have yielded discrepant results. Here, we report the biphasic change of renal beta-catenin expression in mice with overload proteinuria in which beta-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 beta-catenin. Interestingly, a rebound in albuminuria at 8 weeks was accompanied by downregulated tubular beta-catenin expression and heightened tubular apoptosis. In addition, there was an inverse relationship between Dickkopf-3 (Dkk-3) and renal tubular beta-catenin expression at these time points. In vitro, a similar trend in beta-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 beta-catenin in HK-2 cells. Finally, Dkk-3 expression and secretion was increased after prolonged exposure to albumin, leading to the suppression of intracellular beta-catenin signaling pathway. The effect of Dkk-3 on beta-catenin signaling was confirmed by incubation with exogenous Dkk-3 in HK-2 cells. Taken together, these data suggest that downregulation of tubular beta-catenin signaling induced by Dkk-3 has a detrimental role in chronic proteinuria, partially through the increase in apoptosis.