Abstract
The WNT–β-catenin system is an evolutionary conserved signalling pathway that is of particular importance for morphogenesis and cell organization during embryogenesis. The system is usually suppressed in adulthood; however, it can be re-activated in organ injury and regeneration. WNT-deficient mice display severe kidney defects at birth. Transient WNT–β-catenin activation stimulates tissue regeneration after acute kidney injury, whereas sustained (uncontrolled) WNT–β-catenin signalling promotes kidney fibrosis in chronic kidney disease (CKD), podocyte injury and proteinuria, persistent tissue damage during acute kidney injury and cystic kidney diseases. Additionally, WNT–β-catenin signalling is involved in CKD-associated vascular calcification and mineral bone disease. The WNT–β-catenin pathway is tightly regulated, for example, by proteins of the Dickkopf (DKK) family. In particular, DKK3 is released by ‘stressed’ tubular epithelial cells; DKK3 drives kidney fibrosis and is associated with short-term risk of CKD progression and acute kidney injury. Thus, targeting the WNT–β-catenin pathway might represent a promising therapeutic strategy in kidney injury and associated complications.
Key points
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WNT–β-catenin is key regulator of embryogenesis and tissue organization.
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WNT–β-catenin can be re-expressed in adult life in a variety of disease conditions.
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Transient WNT–β-catenin signalling induces repair and regeneration during acute kidney injury, whereas sustained (uncontrolled) WNT–β-catenin signalling promotes kidney fibrosis, podocyte damage and mineral bone disease associated with chronic kidney disease.
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Dickkopf 3 is a WNT–β-catenin modulator that drives kidney fibrosis and represents a novel marker for chronic kidney disease progression and acute kidney injury.
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Several WNT–β-catenin signalling inhibitors are in development, of which so far only the sclerostin-inhibiting antibody is available for treatment of osteoporosis.
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Future studies will improve understanding of the regulation of WNT–β-catenin and set the stage for specific therapies.
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S.J.S., T.S., J.F. and D.F. are supported by the Deutsche Forschungsgemeinschaft (DFG SFB-TRR 219).
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Schunk, S.J., Floege, J., Fliser, D. et al. WNT–β-catenin signalling — a versatile player in kidney injury and repair. Nat Rev Nephrol 17, 172–184 (2021). https://doi.org/10.1038/s41581-020-00343-w
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DOI: https://doi.org/10.1038/s41581-020-00343-w
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