Multiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/β-Catenin Signaling
- 1 January 2015
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 26 (1), 107-120
- https://doi.org/10.1681/asn.2014010085
Abstract
Activation of the renin-angiotensin system (RAS) plays an essential role in the pathogenesis of CKD and cardiovascular disease. However, current anti-RAS therapy only has limited efficacy, partly because of compensatory upregulation of renin expression. Therefore, a treatment strategy to simultaneously target multiple RAS genes is necessary to achieve greater efficacy. By bioinformatics analyses, we discovered that the promoter regions of all RAS genes contained putative T-cell factor (TCF)/lymphoid enhancer factor (LEF)-binding sites, and β-catenin induced the binding of LEF-1 to these sites in kidney tubular cells. Overexpression of either β-catenin or different Wnt ligands induced the expression of all RAS genes. Conversely, a small-molecule β-catenin inhibitor ICG-001 abolished RAS induction. In a mouse model of nephropathy induced by adriamycin, either transient therapy or late administration of ICG-001 abolished established proteinuria and kidney lesions. ICG-001 inhibited renal expression of multiple RAS genes in vivo and abolished the expression of other Wnt/β-catenin target genes. Moreover, ICG-001 therapy restored expression of nephrin, podocin, and Wilms’ tumor 1, attenuated interstitial myofibroblast activation, repressed matrix expression, and inhibited renal inflammation and fibrosis. Collectively, these studies identify all RAS genes as novel downstream targets of Wnt/β-catenin. Our results indicate that blockade of Wnt/β-catenin signaling can simultaneously repress multiple RAS genes, thereby leading to the reversal of established proteinuria and kidney injury.Keywords
This publication has 52 references indexed in Scilit:
- Inhibition of integrin-linked kinase blocks podocyte epithelial–mesenchymal transition and ameliorates proteinuriaKidney International, 2010
- Regulation of Frizzled-Dependent Planar Polarity Signaling by a V-ATPase SubunitCurrent Biology, 2010
- -Catenin mediates adriamycin-induced albuminuria and podocyte injury in adult mouse kidneysNephrology Dialysis Transplantation, 2010
- Requirement of Prorenin Receptor and Vacuolar H + -ATPase–Mediated Acidification for Wnt SignalingScience, 2010
- The Biology of the (Pro)Renin ReceptorJournal of the American Society of Nephrology, 2010
- Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathyKidney International, 2009
- Feasibility of combined treatment with enalapril and candesartan in advanced chronic kidney diseaseNephrology Dialysis Transplantation, 2009
- Wnt Pathway Regulation in Chronic Renal Allograft DamageAmerican Journal of Transplantation, 2009
- Inhibition of the Renin-Angiotensin System in Chronic Kidney Disease: A Critical Look to Single and Dual BlockadeNephron Clinical Practice, 2009
- Wnt/β-Catenin Signaling Promotes Podocyte Dysfunction and AlbuminuriaJournal of the American Society of Nephrology, 2009