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

• Published in: FEBS letters Vol. 585; no. 3; pp. 531 - 538
• Main Authors: Rooney, Brian, O’Donovan, Helen, Gaffney, Andrew, Browne, Marie, Faherty, Noel, Curran, Simon P., Sadlier, Denise, Godson, Catherine, Brazil, Derek P., Crean, John
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 04.02.2011
• Subjects: Animals; beta Catenin - metabolism; Cells, Cultured; Connective tissue growth factor; Connective Tissue Growth Factor - genetics; Connective Tissue Growth Factor - metabolism; Diabetes Mellitus, Type 1 - chemically induced; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic Nephropathies - physiopathology; Diabetic nephropathy; gene expression regulation; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Glycogen synthase kinase 3β; Humans; hyperglycemia; Hyperglycemia - metabolism; hypertension; Hypertension - metabolism; in vitro studies; Kidney Cortex - metabolism; Kidney Cortex - pathology; LDL-Receptor Related Proteins - genetics; LDL-Receptor Related Proteins - metabolism; Low Density Lipoprotein Receptor-Related Protein-6; LRP6; Male; Mesangial Cells - cytology; Mesangial Cells - metabolism; Mice; Mice, Inbred C57BL; microarray technology; pathogenesis; patients; Phosphorylation; Protein Transport; RNA, Small Interfering; Signal Transduction; small interfering RNA; Ureteral Obstruction - metabolism; Ureteral Obstruction - pathology; Wnt; Wnt Proteins - metabolism; β-Catenin; Connective tissue growth factor; β-Catenin; Diabetic nephropathy; Wnt; Glycogen synthase kinase 3β; LRP6
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2011.01.004

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.