JOURNAL ARTICLE
REVIEW

Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease

Lili Zhou, Youhua Liu
Nature Reviews. Nephrology 2015, 11 (9): 535-45
26055352
Podocytes are unique, highly specialized, terminally differentiated cells that are integral components of the kidney glomerular filtration barrier. Podocytes are vulnerable to a variety of injuries and in response they undergo a series of changes ranging from hypertrophy, autophagy, dedifferentiation, mesenchymal transition and detachment to apoptosis, depending on the nature and extent of the insult. Emerging evidence indicates that Wnt/β-catenin signalling has a central role in mediating podocyte dysfunction and proteinuria. Wnts are induced and β-catenin is activated in podocytes in various proteinuric kidney diseases. Genetic or pharmacologic activation of β-catenin is sufficient to impair podocyte integrity and causes proteinuria in healthy mice, whereas podocyte-specific ablation of β-catenin protects against proteinuria after kidney injury. Mechanistically, Wnt/β-catenin controls the expression of several key mediators implicated in podocytopathies, including Snail1, the renin-angiotensin system and matrix metalloproteinase 7. Wnt/β-catenin also negatively regulates Wilms tumour protein, a crucial transcription factor that safeguards podocyte integrity. Targeted inhibition of Wnt/β-catenin signalling preserves podocyte integrity and ameliorates proteinuria in animal models. This Review highlights advances in our understanding of the pathomechanisms of Wnt/β-catenin signalling in mediating podocyte injury, and describes the therapeutic potential of targeting this pathway for the treatment of proteinuric kidney disease.

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