Effect of inhibition of CBP-coactivated β-catenin-mediated Wnt signalling in uremic rats with vascular calcifications

• DOI: 10.1371/journal.pone.0201936
• Publication Date: 2018-08-03T16:00:51Z
• Authors: Eva Gravesen; Anders Nordholm; Maria Mace; Marya Morevati; Estrid Høgdall; Carsten Nielsen; Andreas Kjær; Klaus Olgaard; Ewa Lewin
• Keywords: Male; 0301 basic medicine; 570; Science; Pyrimidinones; Bone and Bones; 03 medical and health sciences; Animals; Vascular Calcification; Wnt Signaling Pathway; beta Catenin; Uremia; Minerals; Q; R; X-Ray Microtomography; Bridged Bicyclo Compounds, Heterocyclic; CREB-Binding Protein; Rats; 3. Good health; Disease Models, Animal; Gene Expression Regulation; Organ Specificity; Medicine; Kidney Failure, Chronic; Biomarkers; Research Article

Uremic vascular calcification is a regulated cell-mediated process wherein cells in the arterial wall transdifferentiate to actively calcifying cells resulting in a process resembling bone formation. Wnt signalling is established as a major driver for vessel formation and maturation and for embryonic bone formation, and disturbed Wnt signalling might play a role in vascular calcification. ICG-001 is a small molecule Wnt inhibitor that specifically targets the coactivator CREB binding protein (CBP)/β-catenin-mediated signalling. In the present investigation we examined the effect of ICG-001 on vascular calcification in uremic rats. Uremic vascular calcification was induced in adult male rats by 5/6-nephrectomy, high phosphate diet and alfacalcidol. The presence of uremic vascular calcification in the aorta was associated with induction of gene expression of the Wnt target gene and marker of proliferation, cyclinD1; the mediator of canonical Wnt signalling, β-catenin and the matricellular proteins, fibronectin and periostin. Furthermore, genes from fibrosis-related pathways, TGF-β and activin A, as well as factors related to epithelial-mesenchymal transition, snail1 and vimentin were induced. ICG-001 treatment had significant effects on gene expression in kidney and aorta from healthy rats. These effects were however limited in uremic rats, and treatment with ICG-001 did not reduce the Ca-content of the uremic vasculature.