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

Abstract

Edited by Lukas Huber Keywords:Connective tissue growth factor Wnt Glycogen synthase kinase 3b b-Catenin LRP6 Diabetic nephropathy a b s t r a c tWe describe the activation of Wnt signalling in mesangial cells by CCN2. CCN2 stimulates phosphorylation of LRP6 and GSK-3b resulting in accumulation and nuclear localisation of b-catenin, TCF/LEF activity and expression of Wnt targets. This is coincident with decreased phosphorylation of b-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. b-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.

Connective tissue growth factor induces tubular epithelial to mesenchymal transition through the activation of canonical Wnt signalingin vitro

“…[9][10][11][12] Our study demonstrated that the Wnt co-receptor LRP6 was expressed in HK-2 cell in vitro. Meanwhile, corresponding with the studies in embryos of X. laevis and primary human mesangial cells, 13,14 we also found rhCTGF initiated the phosphorylation of LRP6 (Ser 1490), which suggests that CTGF may function as an LRP6 ligand in HK-2 cells. In canonical Wnt signaling pathway, the LRP6 intracellular domain can directly promote phosphorylation of GSK-3b.…”

“…9 Importantly, it was reported that in Xenopus laevis embryos and in mesangial cells, CTGF modulated Wnt signaling by binding to lipoprotein receptor-related protein (LRP6). 13,14 On the basis of the previous studies, we hypothesized that canonical Wnt signaling pathway can be activated by CTGF, and tubular EMT can be induced by activation of canonical Wnt signaling pathway in human renal proximal tubular epithelial cells (HK-2) in vitro. In this study, Dickkopf (Dkk)-1, the endogenous LRP6 receptor antagonist, was used to investigate the mechanism of CTGF-induced EMT, and we examined whether CTGF-LRP6 interactions activate canonical Wnt signaling pathway, which contributes indirectly to EMT in tubular epithelial cells in vitro.…”

CTGF mediates high-glucose induced epithelial–mesenchymal transition through activation of β-catenin in podocytes

“…31 Another study in DN demonstrated that CTGF activated Wnt signaling in mesangial cells through LRP6, resulting in the activation of b-catenin promotion of DN. 32 In this research, we found that podocytes underwent EMT in high-glucose milieu; in addition, high glucose induced overexpression of CTGF and nuclear b-catenin in podocytes. Moreover, high glucose-induced EMT and b-catenin overexpression in podocytes were attenuated by anti-CTGF antibody.…”

CCN2 in orofacial tissue development and remodeling

“…This interaction with a variety of collaborators enables CCN2 to execute apparently contradictory missions, i.e., cell growth and differentiation under the physiological state as well as malignant transformation and benign conversion under the pathological state. Additionally, direct activation of intracellular signaling can be triggered through several cell-surface receptors, such as integrins, LRP1, LRP6, and Trk A, to which particular ligands other than CCN2 are already specified [7,10,23,24]. Surprisingly, the direct interaction between the intracellular estrogen receptor and CCN2 and its functional significance have also been recently Alzheimer's disease suggested [22].…”