Gremlin activates the smad pathway linked to epithelial mesenchymal transdifferentiation in cultured tubular epithelial cells
Entity
UAM. Departamento de Medicina; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)Publisher
Hindawi Publishing CorporationDate
2014-01-01Citation
10.1155/2014/802841
BioMed Research International 2014 (2014): 802841
ISSN
2314-6133 (print); 2314-6141 (online)DOI
10.1155/2014/802841Funded by
This work was supported by grants from the Instituto de Salud Carlos III (PI11/01854 and REDINREN ISCIIIRETIC RD12/0021/0002 and 0001), Sociedad Española de Nefrología, PCI Iberoamerica (A/9571/07), CYTED IBERERC, FONDECYT Chile 1080083 and 1120480, Comunidad de Madrid (Fibroteam S2010/BMD-2321, S2010/BMD- 2378), Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín Entralgo/CM) to A.O. Fundación para el fomento en Asturias de la investigaciónn cientíica aplicada y la tecnología (FICYT).Project
Comunidad de Madrid. S2010/BMD-2321/FIBROTEAM; Comunidad de Madrid. S2010/BMD-2378/CIFRAEditor's Version
http://dx.doi.org/10.1155/2014/802841Subjects
Gremlin; Renal cells; MedicinaRights
Copyright © 2014 Raquel Rodrigues-Diez et al.Abstract
Gremlin is a developmental gene upregulated in human chronic kidney disease and in renal cells in response to transforming
growth factor-(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 showthatGremlin 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 Gremlininduced
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
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Google Scholar:Rodrigues Díez, Raquel
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Rodrigues Díez, Raúl
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Lavoz, Carolina
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Carvajal, Gisselle
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Droguett, Alejandra
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García Redondo, Ana Belén
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Rodríguez, Isabel
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Ortiz Arduán, Alberto
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Egido de los Ríos, Jesús
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Mezzano, Sergio
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Ruiz Ortega, Marta
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