Wnt Signaling in Kidney Development and Disease

Abstract

Wnt signal cascade is an evolutionarily conserved, developmental pathway that regulates embryogenesis, injury repair, and pathogenesis of human diseases. It is well established that Wnt ligands transmit their signal via canonical, β-catenin-dependent and noncanonical, β-catenin-independent mechanisms. Mounting evidence has revealed that Wnt signaling plays a key role in controlling early nephrogenesis and is implicated in the development of various kidney disorders. Dysregulations of Wnt expression cause a variety of developmental abnormalities and human diseases, such as congenital anomalies of the kidney and urinary tract, cystic kidney, and renal carcinoma. Multiple Wnt ligands, their receptors, and transcriptional targets are upregulated during nephron formation, which is crucial for mediating the reciprocal interaction between primordial tissues of ureteric bud and metanephric mesenchyme. Renal cysts are also associated with disrupted Wnt signaling. In addition, Wnt components are important players in renal tumorigenesis. Activation of Wnt/β-catenin is instrumental for tubular repair and regeneration after acute kidney injury. However, sustained activation of this signal cascade is linked to chronic kidney diseases and renal fibrosis in patients and experimental animal models. Mechanistically, Wnt signaling controls a diverse array of biologic processes, such as cell cycle progression, cell polarity and migration, cilia biology, and activation of renin-angiotensin system. In this chapter, we have reviewed recent findings that implicate Wnt signaling in kidney development and diseases. Targeting this signaling may hold promise for future treatment of kidney disorders in patients.

Keywords: Wnt ligands; acute kidney injury; chronic kidney disease; nephrogenesis; renal fibrosis; renin–angiotensin system; β-catenin.

Fig. 1

Different Wnt signaling pathways. (A) Canonical Wnt/β-catenin signal pathway. When the signal is in “ON” state, Wnt ligands bind to Frizzled (Fzd) receptors and LRP5/6 coreceptors, which causes Dishevelled (Dvl) to inhibit the β-catenin destruction complex consisting of adenomatous polyposis coli (APC), Axin, and GSK-3β. Pro(renin) receptor (PRR) is also an obligatory component of the Wnt receptor complex and required for canonical Wnt/β-catenin signaling. Stabilized β-catenin is able to enter the nucleus and acts with T cell factor (TCF)/lymphoid enhancer-binding factor (LEF) transcription factor for specific gene expression. When the signal is “OFF,” Dvl cannot act on the destruction complex and β-catenin is then phosphorylated by GSK-3β, leading phosphorylated β-catenin for degradation by ubiquitin (Ub)-proteasome system. (B) Noncanonical Wnt/PCP signal pathway. In Wnt/PCP pathway, Wnt ligands can bind Fzd, Vangl2, and PTK7, then acts with Rho/Rac1 small GTPases and JNK kinases through Dvl. Subsequently, cytoskeleton organization and cell migration are regulated in response to the signal. Daam1 acts with Dvl for downstream effectors, while Prickle inhibits this function. (C) Noncanonical Wnt/Ca²⁺ pathway. Wnt ligand binding activates Fzd/Dvl and induces a rise in intracellular Ca²⁺ levels. Elevated intracellular Ca²⁺ activates calcium calmodulin-dependent protein kinase II (CaMKII), calcinurin (CaN), and protein kinase C (PKC), which activate nuclear transcription factors (NFAT and NF-κB) and promote the expression of downstream target genes.

Fig. 2

Diagram depicts the major events in mammalian nephrogenesis. There are three stages of kidney development in a temporal sequence: pronephros, mesonephros, and metanephros. The pronephros develops at embryonic day 8.5 (E8.5) in mice. The mesonephros develops by the formation of mesonephric tubules from the intermediate mesoderm. The metanephros, begins at E10.5 in mice, finally becomes the permanent and functional kidney in mammalians. MM, Metanephric mesenchyme; ND, nephric duct; UB, ureteric bud; WD, Wolffian ducts.

Fig. 3

Wnt/β-catenin signaling is activated during kidney development. (A) Diagram depicts the construction of the Wnt/β-catenin responsive reporter TOPgal mice. (B–E) Wnt/β-catenin is activated in different time points during kidney development. The black lines in Panels B and C indicate dissection planes for corresponding embryonic kidneys of Panels D and E, respectively. At E10.5 (D) and E12.5 (E), Wnt/β-catenin signaling reporter TOPgal is activated in the nephric tube (NT), Wolffian ducts (WD), and metanephric mesenchyme (MM). (F–G) GSK-3β inhibition by lithium chloride leads to β-catenin-mediated gene expression in TOPgal reporter mice. Maternal injection of the Wnt agonist LiCl significantly enhanced the activity of the reporter β-galactosidase (G), compared with the NaCl-treated mouse embryonic kidneys (F). LEF, Lymphoid enhancer-binding factor; TCF, T cell factor; UB, ureteric bud.