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Review
. 2015 Sep;11(9):535-45.
doi: 10.1038/nrneph.2015.88. Epub 2015 Jun 9.

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

Lili Zhou  1 , Youhua Liu  1   2
Affiliations
Review

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

Lili Zhou et al. Nat Rev Nephrol. 2015 Sep.

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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Figures

Figure 1
Figure 1
The spectrum of podocyte responses after injury. Podocytes respond to injurious stimuli in different ways, depending on the severity and duration of the injury. These responses include hypertrophy, autophagy, dedifferentiation, EMT, detachment and apoptosis. The nature and consequences of these responses are quite different. The processes of hypertrophy and autophagy (stage I) are adaptive and protective. By contrast, the processes of EMT and dedifferentiation (stage II) are maladaptive and can lead to proteinuria, whereas the processes of detachment and apoptosis (stage III) are catastrophic and lead to proteinuria and glomerulosclerosis. The maladaptive changes of podocytes after injury are consistent with the characteristic features of EMT, in which podocytes lose their podocyte-specific markers and gain markers of mesenchymal cells. Abbreviations: EMT, epithelial-to-mesenchymal transition; Fsp-1, fibroblast-specific protein 1; ILK, integrin-linked kinase; MMP-7, matrix metalloproteinase-7; WT1, Wilms tumour protein.
Figure 2
Figure 2
Wnt/β-catenin signalling is activated in the injured kidney and exerts its effects by inducing transcription of target genes. a | Immunohistochemical staining shows podocyte-specific induction of Wnt1 protein (arrows) in a kidney biopsy sample from a patient with FSGS. b | Targets of Wnt/β-catenin that are involved in pathways of podocyte injury and/or dysfunction. Target genes include those that encode Snail1, components of the RAS, MMP-7, TRPC6, Fsp-1, PAI-1 and fibronectin, with various effects on other pathways and cell function. Abbreviations: AGT, angiotensinogen; AT1, angiotensin II type 1 receptor; EMT, epithelial-to-mesenchymal transition; FSGS, focal segmental glomerulosclerosis; Fsp1, fibroblast-specific protein 1; GBM, glomerular basement membrane; MMP-7, matrix metalloproteinase 7; PAI-1, plasminogen activator inhibitor-1; RAS, renin–angiotensin system; TRPC6, transient receptor potential channel 6. Permission for part a obtained from the American Society of Nephrology © Dai, C. et al. J. Am. Soc. Nephrol. 20, 1997-2008 (2009).
Figure 3
Figure 3
The interplay between Wnt/β-catenin signalling and WT1 dictates podocyte health and disease. Wnt/β-catenin and WT1, acting in a Yin–Yang relationship, antagonize each other. These master regulators have opposing roles in podocyte biology; their ratio dictates the state of podocyte health (differentiation) and disease (dysfunction) in vivo. Abbreviations: Fsp-1, fibroblast-specific protein 1; MMP-7, matrix metalloproteinase 7; RAS, renin–angiotensin system; TRPC6, transient receptor potential channel 6; WT1, Wilms tumour protein.
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