Basic ResearchMultiple Genes of the Renin-Angiotensin System Are Novel Targets of Wnt/β-Catenin SignalingZhou, Lili*,†; Li, Yingjian*; Hao, Sha*; Zhou, Dong*; Tan, Roderick J.‡; Nie, Jing†; Hou, Fan Fan†; Kahn, Michael§; Liu, Youhua*,† Author Information *Departments of Pathology and ‡Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; †State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and §Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California Correspondence: Dr. Youhua Liu, Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Email: [email protected] Received January 21, 2014 Accepted April 17, 2014 Journal of the American Society of Nephrology 26(1):p 107-120, January 2015. | DOI: 10.1681/ASN.2014010085 Buy Metrics 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. Copyright © 2015 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.