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

Brian Rooney; Helen O'Donovan; Andrew Gaffney; Marie Browne; Noel Faherty; Simon P Curran; Denise Sadlier; Catherine Godson; Derek P Brazil; John Crean

doi:10.1016/j.febslet.2011.01.004

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

FEBS Lett. 2011 Feb 4;585(3):531-8. doi: 10.1016/j.febslet.2011.01.004. Epub 2011 Jan 14.

Authors

Brian Rooney¹, Helen O'Donovan, Andrew Gaffney, Marie Browne, Noel Faherty, Simon P Curran, Denise Sadlier, Catherine Godson, Derek P Brazil, John Crean

Affiliation

¹ UCD Diabetes Research Centre, UCD School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Ireland.

PMID: 21237163
DOI: 10.1016/j.febslet.2011.01.004

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
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
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Humans
Hyperglycemia / metabolism
Hypertension / metabolism
Kidney Cortex / metabolism
Kidney Cortex / pathology
LDL-Receptor Related Proteins / genetics
LDL-Receptor Related Proteins / metabolism*
Low Density Lipoprotein Receptor-Related Protein-6
Male
Mesangial Cells / cytology
Mesangial Cells / metabolism*
Mice
Mice, Inbred C57BL
Phosphorylation
Protein Transport
RNA, Small Interfering
Signal Transduction*
Ureteral Obstruction / metabolism
Ureteral Obstruction / pathology
Wnt Proteins / metabolism*
beta Catenin / metabolism

Substances

CCN2 protein, mouse
CTNNB1 protein, mouse
LDL-Receptor Related Proteins
LRP6 protein, human
Low Density Lipoprotein Receptor-Related Protein-6
Lrp6 protein, mouse
RNA, Small Interfering
Wnt Proteins
beta Catenin
Connective Tissue Growth Factor
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Glycogen Synthase Kinase 3