Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling.
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.
['Zhou|Lili|L|', 'Li|Yingjian|Y|', 'Hao|Sha|S|', 'Zhou|Dong|D|', 'Tan|Roderick J|RJ|', 'Nie|Jing|J|', 'Hou|Fan Fan|FF|', 'Kahn|Michael|M|', 'Liu|Youhua|Y|']
D000418:Albumins D000818:Animals D001665:Binding Sites D019086:Bridged Bicyclo Compounds, Heterocyclic D002460:Cell Line D019295:Computational Biology D003404:Creatinine D004195:Disease Models, Animal D005786:Gene Expression Regulation D006801:Humans D007668:Kidney D007684:Kidney Tubules D008024:Ligands D051379:Mice D008807:Mice, Inbred BALB C D050199:Podocytes D011401:Promoter Regions, Genetic D011507:Proteinuria D011744:Pyrimidinones D012084:Renin-Angiotensin System D060449:Wnt Signaling Pathway D051176:beta Catenin D018631:ras Proteins
Wnt β-catenin CKD renal fibrosis renin angiotensin system