title: Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease.
abstract: Progressive kidney fibrosis contributes greatly to end-stage renal failure, and no specific treatment is available to preserve organ function. During renal fibrosis, myofibroblasts accumulate in the interstitium of the kidney, leading to massive deposition of extracellular matrix and organ dysfunction. The origin of myofibroblasts is manifold, but the contribution of an epithelial-to-mesenchymal transition (EMT) undergone by renal epithelial cells during kidney fibrosis is still debated. We show that the reactivation of Snai1 (encoding snail family zinc finger 1, known as Snail1) in mouse renal epithelial cells is required for the development of fibrosis in the kidney. Damage-mediated Snail1 reactivation induces a partial EMT in tubular epithelial cells that, without directly contributing to the myofibroblast population, relays signals to the interstitium to promote myofibroblast differentiation and fibrogenesis and to sustain inflammation. We also show that Snail1-induced fibrosis can be reversed in vivo and that obstructive nephropathy can be therapeutically ameliorated in mice by targeting Snail1 expression. These results reconcile conflicting data on the role of the EMT in renal fibrosis and provide avenues for the design of novel anti-fibrotic therapies.
authors.affiliation: Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Grande
authors.affiliation: Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Sánchez-Laorden
authors.affiliation: Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Blau
authors.affiliation: Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: Cristina A
authors.initials: CA
authors.lastname: De Frutos
authors.affiliation: Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: Agnès
authors.initials: A
authors.lastname: Boutet
authors.affiliation: University of Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.|Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Arévalo
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
authors.affiliation: University of Salamanca, Campus Miguel de Unamuno, Salamanca, Spain.|Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: López-Novoa
authors.affiliation: Instituto de Neurociencias Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, San Juan de Alicante, Spain.
authors.forename: M Angela
authors.initials: MA
authors.lastname: Nieto
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D005492:Folic Acid / Q000633:toxicity; D007249:Inflammation / Q000209:etiology; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051436:Renal Insufficiency, Chronic / Q000209:etiology; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000502:physiology*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D005492:Folic Acid