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

Nature Reviews Nephrology volume 11, pages 535–545 (2015)Cite this article

Subjects

Key Points

  • Podocytes are susceptible to various glomerular injuries and undergo a series of adaptive, maladaptive or catastrophic responses, depending on the severity and duration of the insult

  • Wnt/β-catenin signalling is activated in glomerular podocytes in a wide variety of proteinuric kidney diseases; gain or loss-of-function studies have confirmed a role for Wnt/β-catenin signalling in mediating podocyte dysfunction and proteinuria

  • Wnt/β-catenin controls the transcription of a battery of target genes such as Snail1, MMP-7 and Fsp1, and mediates podocyte dedifferentiation and mesenchymal transition, thereby inducing podocytopathy and proteinuria

  • Wnt/β-catenin suppresses Wilms tumour protein, a key transcription factor that safeguards podocyte integrity through ubiquitin-mediated, proteasome-dependent protein degradation

  • Targeted inhibition of Wnt/β-catenin signalling by a variety of approaches preserves podocyte integrity, reduces proteinuria and ameliorates kidney damage

Abstract

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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Figure 1: The spectrum of podocyte responses after injury.
Figure 2: Wnt/β-catenin signalling is activated in the injured kidney and exerts its effects by inducing transcription of target genes.
Figure 3: The interplay between Wnt/β-catenin signalling and WT1 dictates podocyte health and disease.

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Acknowledgements

We apologize to our colleagues whose important findings could not be cited in this article due to space limitations. Reviews were often cited at the expense of original work. Our own work described in this Review was supported by the National Basic Research Program of China Grant 2012CB517700, National Science Foundation of China Grants 81130011 and 81370839, and NIH Grants DK064005 and DK091239.

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Authors and Affiliations

  1. Division of Nephrology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China

    Lili Zhou & Youhua Liu

  2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, 15261, PA, USA

    Youhua Liu

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  1. Lili Zhou
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  2. Youhua Liu
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Both authors contributed equally to researching the data for the article and to discussions of the content. Y.L. wrote the article. Both authors reviewed and/or edited the manuscript before submission.

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Correspondence to Youhua Liu.

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The authors declare no competing financial interests.

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Zhou, L., Liu, Y. Wnt/β-catenin signalling and podocyte dysfunction in proteinuric kidney disease. Nat Rev Nephrol 11, 535–545 (2015). https://doi.org/10.1038/nrneph.2015.88

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