Repair Problems in Podocytes: Wnt, Notch, and Glomerulosclerosis

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Summary

Wnt/Ctnnb1 and Notch signaling play key roles in kidney development and epithelial cell specification. Recent reports have suggested that these pathways are reactivated in response to injury and in different disease conditions. Studies using genetically modified animal models showed that sustained activation of Notch and Wnt signaling in podocytes are causally related to albuminuria and glomerulosclerosis development. Here, we discuss the role and regulation of Wnt/Ctnnb1 and Notch signaling in podocytes.

Section snippets

Wnt/Ctnnb1 Signaling

Mammalian Wnt signaling was first reported in 1987 by identifying the int1 oncogene, which turned out to be the mammalian homolog of the Drosophila gene wingless (Wg).14, 15 The name “Wnt” was coined by combining “int” and “wingless.” The drosophila armadillo and its mammalian homologue Ctnnb1 then were identified as the major effectors of the Wg/Wnt pathway.16 In mammals, 19 different Wnts and 10 Wnt receptors (Frizzled) have been discovered thus far.17

In the absence of Wnt ligands

Kidney Development and Ctnnb1

Together with other secreted factors such as fibroblast growth factor, transforming growth factor-β (TGF-β),and hedgehog protein, Wnt proteins play a key role in kidney development. Wnt4 is expressed in the early condensate and pretubular aggregates. Wnt4 null mutantmice have severely hypoplastic kidneys, indicating that Wnt4 is necessary for tubulogenesis, especially for mesenchymal-epithelial transformation.20 In the absence of Wnt4, the metanephric mesenchyme condenses normally and the early

Ctnnb1 in Podocytes

Ctnnb1 is a multifunctional protein; it interacts with structural proteins including cadherins. In the absence of Wnt signaling, Ctnnb1 forms a stable complex with E-cadherin and establishes a link with the actin cytoskeleton and participates in adherence junction formation.22 The role and regulation of Ctnnb1 with cadherins and actin cytoskeletal proteins have not been fully explored in podocytes, however, it could be an interesting research area. Once MET and kidney development is complete,

What is the Consequence of Wnt/Ctnnb1 Activation in Podocytes?

The first report describing the consequence of Ctnnb1 activation in podocytes comes from the Liu group.27 Dai et al27 injected Wnt1-expressing plasmid intravenously into mice and successfully induced Ctnnb1 accumulation in podocytes. Although Wnt1 alone did not induce albuminuria, animals developed high-grade proteinuria when they were injected with doxorubicin hydrochloride; even though they were not on an doxorubicin-sensitive background. Interestingly, they also reported that intravenous

What is the Mechanism of Ctnnb1-Induced Changes in Podocytes ?

Mouse models and cultured cell lines were used to answer this question. Liu et al27 proposed that stabilized expression of Ctnnb1 caused epithelial-to-mesenchymal-transition (EMT) of podocytes. The increased expression of Snai1 and the decreased expression of nephrin were interpreted as evidence of podocyte EMT. Kato et al found that podocyte cell lines established from mutant mice or treated with various inhibitors of glycogen synthase kinase-3 beta showed increased survival ability, but they

Does Wnt/Ctnnb1 Inhibition Protect From Albuminuria and Glomerulosclerosis?

Because enhanced expression of Wnt/Ctnnb1 induced albuminuria and glomerulosclerosis, we would expect that inhibition of Ctnnb1 would protect mice from glomerular disease. To answer this question, three independent groups have generated mice with podocyte-specific Ctnnb1 deletion.24, 27, 33 All three groups reported no major histologic changes by light microscopy or albuminuria at baseline. This is consistent with the observation that the Wnt/Ctnnb1 pathway is not required for podocyte

Downstream of Wnt Signaling

To better understand the mechanism by which Wnt signaling controls podocyte phenotype, we performed genome-wide transcript analysis of isolated glomeruli from mice with podocyte-specific deletion and stabilization of Ctnnb1.24 One of the pathways that appeared to be regulated by Wnt signaling was the Notch pathway. During development and differentiation these two pathways often interact and in the kidney they are responsible for the mesenchymal to epithelial transition and tubular epithelial

Notch Signaling in Podocytes

Notch signaling controls cell differentiation in diverse organ systems including the kidney and it is essential for proximal tubule development and podocyte specification.41 Once glomerular development is complete, Notch activity is largely decreased in murine and human glomeruli. Increased glomerular Notch activity has been reported in several different injury models and in patients with chronic glomerular disorders, diabetes, human immunodeficiency virus, FSGS,42, 43 and systemic lupus

Podocyte Repair: Wnt/Ctnnb1, Notch, and Glomerulosclerosis

During the past few years we learned that developmental pathways are re-activated in injured glomeruli, including the Wnt and Notch pathways. The reactivation of these pathways appears to recapitulate observations from phylogenetically lower species, in which Wnt and Notch activation after injury play key roles in the regeneration process (Fig. 1). Therefore, it would seem logical that these pathways are activated in injury to mediate regeneration or repair. Regeneration involves either the

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    Financial support: Supported by the National Institutes of Health (5R01DK076077 and 5R01DK087635-02 to K.S.), and by the Nephcure foundation (H.K.).

    Conflict of interest statement: Dr. Susztak filed patent application for the use of Notch based inhibitors for the cure of chronic kidney disease.

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