title: CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: implications for the pathogenesis of diabetic nephropathy.
abstract: 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.
authors.affiliation: UCD Diabetes Research Centre, UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Brian
authors.initials: B
authors.lastname: Rooney
authors.forename: Helen
authors.initials: H
authors.lastname: O'Donovan
authors.forename: Andrew
authors.initials: A
authors.lastname: Gaffney
authors.forename: Marie
authors.initials: M
authors.lastname: Browne
authors.forename: Noel
authors.initials: N
authors.lastname: Faherty
authors.forename: Simon P
authors.initials: SP
authors.lastname: Curran
authors.forename: Denise
authors.initials: D
authors.lastname: Sadlier
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Derek P
authors.initials: DP
authors.lastname: Brazil
authors.forename: John
authors.initials: J
authors.lastname: Crean
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008297:Male; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D021381:Protein Transport; D034741:RNA, Small Interfering; D015398:Signal Transduction; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C526318:CCN2 protein, mouse; C495267:CTNNB1 protein, mouse; D026502:LDL-Receptor Related Proteins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D055513:Connective Tissue Growth Factor; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3