title: Gremlin activates the Smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells.
abstract: Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming growth factor-β (TGF-β). Epithelial mesenchymal transition (EMT) is one process involved in renal fibrosis. In tubular epithelial cells we have recently described that Gremlin induces EMT and acts as a downstream TGF-β mediator. Our aim was to investigate whether Gremlin participates in EMT by the regulation of the Smad pathway. Stimulation of human tubular epithelial cells (HK2) with Gremlin caused an early activation of the Smad signaling pathway (Smad 2/3 phosphorylation, nuclear translocation, and Smad-dependent gene transcription). The blockade of TGF-β, by a neutralizing antibody against active TGF-β, did not modify Gremlin-induced early Smad activation. These data show that Gremlin directly, by a TGF-β independent process, activates the Smad pathway. In tubular epithelial cells long-term incubation with Gremlin increased TGF-β production and caused a sustained Smad activation and a phenotype conversion into myofibroblasts-like cells. Smad 7 overexpression, which blocks Smad 2/3 activation, diminished EMT changes observed in Gremlin-transfected tubuloepithelial cells. TGF-β neutralization also diminished Gremlin-induced EMT changes. In conclusion, we propose that Gremlin could participate in renal fibrosis by inducing EMT in tubular epithelial cells through activation of Smad pathway and induction of TGF-β.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Rodrigues-Diez
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Raúl R
authors.initials: RR
authors.lastname: Rodrigues-Diez
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Lavoz
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Gisselle
authors.initials: G
authors.lastname: Carvajal
authors.affiliation: Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Droguett
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Garcia-Redondo
authors.affiliation: Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain ; Instituto Reina Sofía de Investigación Nefrológica, 28003 Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Instituto Reina Sofía de Investigación Nefrológica, 28003 Madrid, Spain ; Division of Dialysis, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Instituto Reina Sofía de Investigación Nefrológica, 28003 Madrid, Spain ; Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, CIBERDEM, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile.
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D002460:Cell Line; D054338:Cell Transdifferentiation / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis*
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1