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.

Download full-text


Available from: Catherine Godson, Aug 19, 2014
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    12/2013; 2013(3):987064. DOI:10.1155/2013/987064
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Unresolved inflammation underlies the development of fibrosis and organ failure. Here, we investigate the potential of the proresolving eicosanoid lipoxinA₄ (LXA₄) and its synthetic analog benzo-LXA₄ to prophylactically modulate fibrotic and inflammatory responses in a model of early renal fibrosis, unilateral ureteric obstruction (UUO). Male Wistar rats (Animalia, Chordata, Rattus norvegicus) were injected intravenously with vehicle (0.1% ethanol), LXA₄ (45 μg/250-g rat), or benzo-LXA₄ (15 μg/250-g rat) 15 min prior to surgery and sacrificed 3 d postligation. Renal gene and protein expression, collagen deposition, macrophage infiltration, and apoptosis were analyzed using manipulated kidneys from sham operations as control. Lipoxins (LXs) attenuated collagen deposition and renal apoptosis (P<0.05) and shifted the inflammatory milieu toward resolution, inhibiting TNF-α and IFN-γ expression, while stimulating proresolving IL-10. LXs attenuated UUO-induced activation of MAP kinases, Akt, and Smads (P<0.05) in injured kidneys. We explored whether the underlying mechanism reflected LX-induced modulation of fibroblast activation. Using cultured rat renal NRK-49F fibroblasts, we report that LXA₄ (1 nM) inhibits TGF-β1 (10 ng/ml)-induced activation of Smad2 and MAP-kinases (P<0.05), and furthermore, LXA₄ reduced TGF-β1-stimulated PAI-1 luciferase activation (P<0.05) relative to vehicle-stimulated cells. We propose that LXs may represent a potentially useful and novel therapeutic strategy for consideration in the context of renal fibrosis.
    The FASEB Journal 05/2011; 25(9):2967-79. DOI:10.1096/fj.11-185017 · 5.04 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vascular calcification increasingly afflicts our aging, dysmetabolic population. Once considered only a passive process of dead and dying cells, vascular calcification has now emerged as a highly regulated form of biomineralization organized by collagenous and elastin extracellular matrices. During skeletal bone formation, paracrine epithelial-mesenchymal and endothelial-mesenchymal interactions control osteochondrocytic differentiation of multipotent mesenchymal progenitor cells. These paracrine osteogenic signals, mediated by potent morphogens of the bone morphogenetic protein and wingless-type MMTV integration site family member (Wnt) superfamilies, are also active in the programming of arterial osteoprogenitor cells during vascular and valve calcification. Inflammatory cytokines, reactive oxygen species, and oxylipids-increased in the clinical settings of atherosclerosis, diabetes, and uremia that promote arteriosclerotic calcification-elicit the ectopic vascular activation of osteogenic morphogens. Specific extracellular and intracellular inhibitors of bone morphogenetic protein-Wnt signaling have been identified as contributing to the regulation of osteogenic mineralization during development and disease. These inhibitory pathways and their regulators afford the development of novel therapeutic strategies to prevent and treat valve and vascular sclerosis.
    Circulation Research 08/2011; 109(5):564-77. DOI:10.1161/CIRCRESAHA.110.234278 · 11.02 Impact Factor
Show more