title: Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling.
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.
authors.affiliation: Departments of Pathology and State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Departments of Pathology and.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Departments of Pathology and.
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.affiliation: Departments of Pathology and.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Tan
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Jing
authors.initials: J
authors.lastname: Nie
authors.affiliation: State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.affiliation: Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.affiliation: Departments of Pathology and State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; and liuy@upmc.edu.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000418:Albumins / Q000737:chemistry; D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D002460:Cell Line; D019295:Computational Biology; D003404:Creatinine / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D050199:Podocytes / Q000166:cytology; D011401:Promoter Regions, Genetic; D011507:Proteinuria / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry; D012084:Renin-Angiotensin System / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000418:Albumins; D019086:Bridged Bicyclo Compounds, Heterocyclic; C492448:ICG 001; D008024:Ligands; D011744:Pyrimidinones; D051176:beta Catenin; D003404:Creatinine; D018631:ras Proteins
keywords: CKD; Wnt; renal fibrosis; renin angiotensin system; β-catenin