New insights into the role and mechanism of Wnt/ß-catenin signalling in kidney fibrosis.

ABSTRACT

Wnt/ß-catenin is an evolutionarily conserved, developmental signalling pathway that regulates embryogenesis, injury repair and pathogenesis of human diseases. Dysregulated activation of Wnt/ß-catenin is associated with the development and progression of renal fibrotic lesions after injury. Wnt are induced and ß-catenin is activated in various models of experimental chronic kidney disease (CKD) and in human nephropathies. Recent findings indicate that pro(renin) receptor is an amplifier of Wnt/ß-catenin by acting as a downstream target and an obligatory component for its signal transduction. Genetic blockade of Wnt secretion in a cell type-specific manner uncovers renal tubular epithelium as the major source of Wnt ligands in CKD. Wnt/ß-catenin controls the expression of a wide variety of downstream mediators implicated in kidney fibrosis, such as fibronectin, Snail1, matrix metalloproteinase-7, hepatocyte growth factor and various components of the renin-angiotensin system. Targeted inhibition of Wnt/ß-catenin is able to ameliorate kidney fibrotic lesions in pre-clinical settings. In this review, we summarize recent advances in our understanding of the regulation, signal transduction, role and mechanisms of Wnt/ß-catenin signalling in the pathogenesis of kidney fibrosis. We also discuss the therapeutic potential of targeting this pathway for the treatment of fibrotic CKD.