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BioMed Research International
Volume 2014 (2014), Article ID 802841, 11 pages
http://dx.doi.org/10.1155/2014/802841
Research Article

Gremlin Activates the Smad Pathway Linked to Epithelial Mesenchymal Transdifferentiation in Cultured Tubular Epithelial Cells

1Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain
2Division of Nephrology, School of Medicine, Universidad Austral, Valdivia, Chile
3Bone and Mineral Research Unit, Hospital Universitario Central de Asturias, 33006 Oviedo, Spain
4Instituto Reina Sofía de Investigación Nefrológica, 28003 Madrid, Spain
5Division of Dialysis, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain
6Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, CIBERDEM, Avenida Reyes Católicos 2, 28040 Madrid, Spain

Received 27 February 2014; Revised 25 April 2014; Accepted 1 May 2014; Published 18 May 2014

Academic Editor: Akito Maeshima

Copyright © 2014 Raquel Rodrigues-Diez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.