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.

New insights into the role and mechanism of Wnt/β‐catenin signalling in kidney fibrosis

“…The Wnt family comprises of a group of secreted, lipid‐modified signalling glycoproteins. In mammalian, there are at least 19 members of the Wnt family (for more details, see the Wnt homepage: http://www.stanford.edu/group/nusselab/cgi-bin/wnt), which are critical to kidney development, and defects in Wnt signalling may lead to various human diseases, including developmental abnormalities and cancers …”

“…The Wnt family comprises of a group of secreted, lipidmodified signalling glycoproteins. In mammalian, there are at least 19 members of the Wnt family (for more details, see the Wnt homepage: www.stanford.edu/group/nusselab/cgibin/Wnt), which are critical to kidney development, 13 and defects in Wnt signalling may lead to various human diseases, including developmental abnormalities and cancers. 12 Once secreted from the producing cells, Wnt proteins transmit the signal across the cell membrane through interactions with the Frizzled (Fzd) family of receptors and their co-receptors, the low-density lipoprotein receptor-related protein-5 or -6 (LRP-5/6) of the target cells.…”

“…[7][8][9][10] Wnt/β-catenin is an evolutionarily conserved, developmental signalling pathway implicated in regulating an assortment of biological processes, such as cell fate determination, tissue homeostasis, organ development and pathogenesis of human diseases. [11][12][13] Although quiescent in normal adult kidneys, Wnt/β-catenin is re-activated in various models of kidney injury. Mounting evidence has established a crucial role of this signalling pathway in regulating different kidney responses after injurious insults.…”

“…Wnt/β‐catenin is an evolutionarily conserved, developmental signalling pathway implicated in regulating an assortment of biological processes, such as cell fate determination, tissue homeostasis, organ development and pathogenesis of human diseases . Although quiescent in normal adult kidneys, Wnt/β‐catenin is re‐activated in various models of kidney injury.…”

The emerging role of cellular senescence in renal diseases

“…45 Increased expression of BCL-W and BCL-XL is involved in senescent cell resistance to apoptosis, and inhibition of BCL-W and BCL-XL causes death of senescent cells. 46 According to a recent study, 47 45 In addition, Wnt/β-catenin signalling is involved in the pathogenesis of cellular senescence (Figure 1).…”