Wnts compose a family of signaling proteins that play an essential role in kidney development, but their expression in adult kidney is thought to be silenced. Here, we analyzed the expression and regulation of Wnts and their receptors and antagonists in normal and fibrotic kidneys after obstructive injury. In the normal mouse kidney, the vast majority of 19 different Wnts and 10 frizzled receptor genes was expressed at various levels. After unilateral ureteral obstruction, all members of the Wnt family except Wnt5b, Wnt8b, and Wnt9b were upregulated in the fibrotic kidney with distinct dynamics. In addition, the expression of most Fzd receptors and Wnt antagonists was also induced. Obstructive injury led to a dramatic accumulation of β-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/β-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal β-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal β-catenin accumulation and inhibited the expression of Wnt/β-catenin target genes. Furthermore, gene therapy with Dickkopf-1 inhibited myofibroblast activation; suppressed expression of fibroblast-specific protein 1, type I collagen, and fibronectin; and reduced total collagen content in the model of obstructive nephropathy. In summary, these results establish a role for Wnt/β-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.

The liver is an organ that performs a multitude of functions, and its health is pertinent and indispensable to survival. Thus, the cellular and molecular machinery driving hepatic functions is of utmost relevance. The Wnt signaling pathway is one such signaling cascade that enables hepatic homeostasis and contributes to unique hepatic attributes such as metabolic zonation and regeneration. The Wnt/β-catenin pathway plays a role in almost every facet of liver biology. Furthermore, its aberrant activation is also a hallmark of various hepatic pathologies. In addition to its signaling function, β-catenin also plays a role at adherens junctions. Wnt/β-catenin signaling also influences the function of many different cell types. Due to this myriad of functions, Wnt/β-catenin signaling is complex, context-dependent, and highly regulated. In this review, we discuss the Wnt/β-catenin signaling pathway, its role in cell-cell adhesion and liver function, and the cell type–specific roles of Wnt/β-catenin signaling as it relates to liver physiology and pathobiology.

β-catenin (encoded by CTNNB1) is a subunit of the cell surface cadherin protein complex that acts as an intracellular signal transducer in the WNT signaling pathway; alterations in its activity have been associated with the development of hepatocellular carcinoma and other liver diseases. Other than WNT, additional signaling pathways also can converge at β-catenin. β-catenin also interacts with transcription factors such as T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α to regulate the expression of target genes. We discuss the role of β-catenin in metabolic zonation of the adult liver. β-catenin also regulates the expression of genes that control metabolism of glucose, nutrients, and xenobiotics; alterations in its activity may contribute to the pathogenesis of nonalcoholic steatohepatitis. Alterations in β-catenin signaling may lead to activation of hepatic stellate cells, which is required for fibrosis. Many hepatic tumors such as hepatocellular adenomas, hepatocellular cancers, and hepatoblastomas have mutations in CTNNB1 that result in constitutive activation of β-catenin, so this molecule could be a therapeutic target. We discuss how alterations in β-catenin activity contribute to liver disease and how these might be used in diagnosis and prognosis, as well as in the development of therapeutics.

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/β-catenin signaling plays a critical role in podocyte injury and proteinuria. Treatment with adriamycin induced Wnt and activated β-catenin in mouse podocytes. Overexpression of Wnt1 in vivo activated glomerular β-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 β-catenin protected against development of albuminuria after injury. Moreover, pharmacologic activation of β-catenin induced albuminuria in wild-type mice but not in β-catenin-knockout littermates. In human proteinuric kidney diseases such as diabetic nephropathy and focal segmental glomerulosclerosis, we observed upregulation of Wnt1 and active β-catenin in podocytes. Ectopic expression of either Wnt1 or stabilized β-catenin in vitro induced the transcription factor Snail and suppressed nephrin expression, leading to podocyte dysfunction. These results suggest that targeting hyperactive Wnt/β-catenin signaling may represent a novel therapeutic strategy for proteinuric kidney diseases.