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.
Highlights
Albumin is the most abundant protein in the glomerular filtrate, which is reabsorbed by the proximal tubule via receptor-mediated endocytosis.[3,4] This process activates a range of intracellular signaling pathways in renal cells[5,6,7] and triggers the tubular epithelial cells to enter a proinflammatory state[8] that heralds a profibrotic microenvironment with accumulation of extracellular matrix.[9]
In the canonical Wnt/β-catenin signaling pathway, Wnt molecules in the extracellular matrix transmit the intracellular signal through interacting with Frizzled receptors and co-receptor LDL receptor-related protein (Lrp) 5/6.21,22 This interaction elicits an intracellular signaling cascade resulting in an accumulation of non-phosphorylated β-catenin
Canonical Wnt/β-catenin signaling pathway has been implicated in cystic kidney disease,[24,25] acute kidney injury (AKI) and diabetic nephropathy (DN).[26]
Summary
Albumin is the most abundant protein in the glomerular filtrate, which is reabsorbed by the proximal tubule via receptor-mediated endocytosis.[3,4] This process activates a range of intracellular signaling pathways in renal cells[5,6,7] and triggers the tubular epithelial cells to enter a proinflammatory state[8] that heralds a profibrotic microenvironment with accumulation of extracellular matrix.[9]. An increasing number of experimental investigations and clinical observations have proved renal tubular cell apoptosis in the pathogenesis of renal tubular injury.[13,14,15] Emerging evidence indicates that some underlying tubulotoxic mechanisms of tubular cell death are stimulated by albumin overload.[16]. Canonical Wnt/β-catenin signaling pathway has been implicated in cystic kidney disease,[24,25] acute kidney injury (AKI) and diabetic nephropathy (DN).[26] Recent evidence have indicated that aberrant Wnt/β-catenin activities in renal cells contributed to epithelial–mesenchymal transition (EMT),[27] fibrosis[28,29] and apoptosis during nephropathy.[30]. We presented in vitro and in vivo evidence that protein overload induced apoptosis in proximal tubular epithelial cells (PTECs) via downregulation of Wnt/β-catenin signaling pathway. The upregulation of Dickkopf-3 (Dkk-3) may act as a novel autocrine mechanism that suppresses Wnt/β-catenin signaling upon protein overload in PTECs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
