Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells

Epithelial–mesenchymal transition (EMT) contributes to the progression of renal tubulointerstitial fibrosis. The N-methyl-D-aspartate receptor (NMDAR), which is present in proximal tubular epithelium, is a glutamate receptor that acts as a calcium channel. Activation of NMDAR induces actin rearrange...

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Autores: Bozic, Milica, De Rooij, Johan, Parisi, Eva, Ruiz Ortega, Marta, Fernández, Elvira, Valdivielso, José Manuel
Tipo de recurso: artículo
Fecha de publicación:2011
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/665338
Acceso en línea:http://hdl.handle.net/10486/665338
https://dx.doi.org/10.1681/ASN.2010070701
Access Level:acceso abierto
Palabra clave:Epithelial cells
Cell differentiation
Actins
Fibrosis
Medicina
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spelling Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cellsBozic, MilicaDe Rooij, JohanParisi, EvaRuiz Ortega, MartaFernández, ElviraValdivielso, José ManuelEpithelial cellsCell differentiationActinsFibrosisMedicinaEpithelial–mesenchymal transition (EMT) contributes to the progression of renal tubulointerstitial fibrosis. The N-methyl-D-aspartate receptor (NMDAR), which is present in proximal tubular epithelium, is a glutamate receptor that acts as a calcium channel. Activation of NMDAR induces actin rearrangement in cells of the central nervous system, but whether it helps maintain the epithelial phenotype of the proximal tubule is unknown. Here, knockdown of NMDAR1 in a proximal tubule cell line (HK-2) induced changes in cell morphology, reduced E-cadherin expression, and increased -SMA expression. Induction of EMT with TGF- 1 led to downregulation of both E-cadherin and membrane-associated -catenin, reorganization of F-actin, expression of mesenchymal markers de novo, upregulation of Snail1, and increased cell migration; co-treatment with NMDA attenuated all of these changes. Furthermore, NMDA reduced TGF- 1–induced phosphorylation of Erk1/2 and Akt and the activation of Ras, suggesting that NMDA antagonizes TGF- 1–induced EMT by inhibiting the Ras-MEK pathway. In the unilateral ureteral obstruction model, treatment with NMDA blunted obstruction-induced upregulation of -SMA, FSP1, and collagen I and downregulation of E-cadherin. Taken together, these results suggest that NMDAR plays a critical role in preserving the normal epithelial phenotype and modulating tubular EMTThis work was supported by Grants FIS, PI07/0427, and REDINREN (16/06). M.B. is supported by the studentship of the Catalan Government.American Society of NephrologyDepartamento de MedicinaFacultad de Medicina20112011-06-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10486/665338https://dx.doi.org/10.1681/ASN.2010070701reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/6653382026-06-23T12:46:27Z
dc.title.none.fl_str_mv Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
title Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
spellingShingle Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
Bozic, Milica
Epithelial cells
Cell differentiation
Actins
Fibrosis
Medicina
title_short Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
title_full Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
title_fullStr Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
title_full_unstemmed Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
title_sort Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells
dc.creator.none.fl_str_mv Bozic, Milica
De Rooij, Johan
Parisi, Eva
Ruiz Ortega, Marta
Fernández, Elvira
Valdivielso, José Manuel
author Bozic, Milica
author_facet Bozic, Milica
De Rooij, Johan
Parisi, Eva
Ruiz Ortega, Marta
Fernández, Elvira
Valdivielso, José Manuel
author_role author
author2 De Rooij, Johan
Parisi, Eva
Ruiz Ortega, Marta
Fernández, Elvira
Valdivielso, José Manuel
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Medicina
Facultad de Medicina
dc.subject.none.fl_str_mv Epithelial cells
Cell differentiation
Actins
Fibrosis
Medicina
topic Epithelial cells
Cell differentiation
Actins
Fibrosis
Medicina
description Epithelial–mesenchymal transition (EMT) contributes to the progression of renal tubulointerstitial fibrosis. The N-methyl-D-aspartate receptor (NMDAR), which is present in proximal tubular epithelium, is a glutamate receptor that acts as a calcium channel. Activation of NMDAR induces actin rearrangement in cells of the central nervous system, but whether it helps maintain the epithelial phenotype of the proximal tubule is unknown. Here, knockdown of NMDAR1 in a proximal tubule cell line (HK-2) induced changes in cell morphology, reduced E-cadherin expression, and increased -SMA expression. Induction of EMT with TGF- 1 led to downregulation of both E-cadherin and membrane-associated -catenin, reorganization of F-actin, expression of mesenchymal markers de novo, upregulation of Snail1, and increased cell migration; co-treatment with NMDA attenuated all of these changes. Furthermore, NMDA reduced TGF- 1–induced phosphorylation of Erk1/2 and Akt and the activation of Ras, suggesting that NMDA antagonizes TGF- 1–induced EMT by inhibiting the Ras-MEK pathway. In the unilateral ureteral obstruction model, treatment with NMDA blunted obstruction-induced upregulation of -SMA, FSP1, and collagen I and downregulation of E-cadherin. Taken together, these results suggest that NMDAR plays a critical role in preserving the normal epithelial phenotype and modulating tubular EMT
publishDate 2011
dc.date.none.fl_str_mv 2011
2011-06-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/665338
https://dx.doi.org/10.1681/ASN.2010070701
url http://hdl.handle.net/10486/665338
https://dx.doi.org/10.1681/ASN.2010070701
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv American Society of Nephrology
publisher.none.fl_str_mv American Society of Nephrology
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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