CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: Implications for the pathogenesis of diabetic nephropathy

UCD Diabetes Research Centre, UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
FEBS letters (Impact Factor: 3.17). 02/2011; 585(3):531-8. DOI: 10.1016/j.febslet.2011.01.004
Source: PubMed


We describe the activation of Wnt signalling in mesangial cells by CCN2. CCN2 stimulates phosphorylation of LRP6 and GSK-3β resulting in accumulation and nuclear localisation of β-catenin, TCF/LEF activity and expression of Wnt targets. This is coincident with decreased phosphorylation of β-catenin on Ser 33/37 and increased phosphorylation on Tyr142. DKK-1 and LRP6 siRNA reversed CCN2's effects. Microarray analyses of diabetic patients identified differentially expressed Wnt components. β-Catenin is increased in type 1 diabetic and UUO mice and in in vitro models of hyperglycaemia and hypertension. These findings suggest that Wnt/CCN2 signalling plays a role in the pathogenesis of diabetic nephropathy.

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Available from: Catherine Godson, Aug 19, 2014
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    • "Rooney et al. found that CTGF induced the phosphorylation of LRP6 and GSK-3β, which resulted in an accumulation of β-catenin and its nuclear localization, and activated the transcription factor TCF/LEF and increased MCs apoptosis via the regulation of the expression of Wnt targets. However, treatment with DKK-1, an endogenous LRP6 receptor antagonist or knockdown of LRP6 via siRNA, ameliorated CCN2-induced Wnt signaling activation in human MCs [32]. Moreover, both SERPINA3 K, a serine proteinase inhibitor, and DKK-1 blocked the overproduction of CTGF in cultured renal MCs exposed to HG [28]. "
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    ABSTRACT: The Wnt family of proteins belongs to a group of secreted lipid-modified glycoproteins with highly conserved cysteine residues. Prior results indicate that Wnt/ β -catenin signaling plays a prominent role in cell differentiation, adhesion, survival, and apoptosis and is involved in organ development, tumorigenesis, and tissue fibrosis, among other functions. Accumulating evidence has suggested that Wnt/ β -catenin exhibits a pivotal function in the progression of diabetic nephropathy (DN). In this review, we focused on discussing the dual role of Wnt/ β -catenin in apoptosis and epithelial mesenchymal transition (EMT) formation of mesangial cells. Moreover, we also elucidated the effect of Wnt/ β -catenin in podocyte dysfunction, tubular EMT formation, and renal fibrosis under DN conditions. In addition, the molecular mechanisms involved in this process are introduced. This information provides a novel molecular target of Wnt/ β -catenin for the protection of kidney damage and in delay of the progression of DN.
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    • "Furthermore, it has been described that CTGF can also interact with the CT domain of LRP6, so CTGF is also able to affect the interaction of Wnt with their coreceptor[145,146]. Other studies in human mesangial cells have been described suggesting that CTGF stimulates the canonical Wnt pathway in an LRP6-dependent manner, and this effect is inhibited in the presence of DKK1 (Table 3)[145]. Remarkably, studies in a fibroblast cell line show that the treatment with the Wnt3a ligand, which signals through the Wnt/β-catenin pathway , increases the expression of CTGF and TGF-β mRNAs, reinforcing the view that these signaling pathways may crosstalk in the context of fibrosis[147]. "

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