title: Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells.
abstract: The contribution of angiotensin II (ANG II) to renal and tubular fibrosis has been widely reported. Recent studies have shown that collecting duct cells can undergo mesenchymal transition suggesting that collecting duct cells are involved in interstitial fibrosis. The Wnt/β-catenin signaling pathway plays an essential role in development, organogenesis, and tissue homeostasis; however, the dysregulation of this pathway has been linked to fibrosis. In this study, we investigated whether AT1 receptor activation induces the expression of fibronectin and collagen I via the β-catenin pathway in mouse collecting duct cell line M-1. ANG II (10(-7) M) treatment in M-1 cells increased mRNA, protein levels of fibronectin and collagen I, the β-catenin target genes (cyclin D1 and c-myc), and the myofibroblast phenotype. These effects were prevented by candesartan, an AT1 receptor blocker. Inhibition of the β-catenin degradation with pyrvinium pamoate (pyr; 10(-9) M) prevented the ANG II-induced expression of fibronectin, collagen I, and β-catenin target genes. ANG II treatment promoted the accumulation of β-catenin protein in a time-dependent manner. Because phosphorylation of glycogen synthase kinase-3β (GSK-3β) inhibits β-catenin degradation, we further evaluated the effects of ANG II and ANG II plus pyr on p-ser9-GSK-3β levels. ANG II-dependent upregulation of β-catenin protein levels was correlated with GSK-3β phosphorylation. These effects were prevented by pyr. Our data indicate that in M-1 collecting duct cells, the β-catenin pathway mediates the stimulation of fibronectin and collagen I in response to AT1 receptor activation.
authors.affiliation: Department of Physiology, Center of Aging and Regeneration CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Cell and Molecular Biology, Center of Aging and Regeneration CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Physiology, Tulane University, New Orleans, Louisiana; and.
authors.forename: Catherina A
authors.initials: CA
authors.lastname: Cuevas
authors.affiliation: Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile;
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Gonzalez
authors.affiliation: Department of Cell and Molecular Biology, Center of Aging and Regeneration CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile;
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.affiliation: Department of Physiology, Center of Aging and Regeneration CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile;
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Vio
authors.affiliation: Department of Physiology, Tulane University, New Orleans, Louisiana; and Department of Hypertension and Renal Center of Excellence, Tulane University, New Orleans, Louisiana mprieto@tulane.edu.
authors.forename: Minolfa C
authors.initials: MC
authors.lastname: Prieto
mesh_terms: D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; C495267:CTNNB1 protein, mouse; C530105:Ccnd1 protein, mouse; D024042:Collagen Type I; D005353:Fibronectins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; C544013:alpha-smooth muscle actin, mouse; D051176:beta Catenin; D000804:Angiotensin II; D019938:Cyclin D1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: mouse collecting duct cell; pyrvinium pamoate; tissue homeostasis