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...
| Authors: | ; ; ; ; ; |
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| Format: | Article |
| Publication date: | 2011 |
| Country: | España |
| Institution: | Universidad Autónoma de Madrid |
| Repository: | Biblos-e Archivo. Repositorio Institucional de la UAM |
| Language: | English |
| OAI Identifier: | oai:repositorio.uam.es:10486/665338 |
| Online Access: | http://hdl.handle.net/10486/665338 https://dx.doi.org/10.1681/ASN.2010070701 |
| Access Level: | Open access |
| Keyword: | Epithelial cells Cell differentiation Actins Fibrosis Medicina |
| _version_ | 1878739614995316737 |
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| author | Bozic, Milica |
| author2 | De Rooij, Johan Parisi, Eva Ruiz Ortega, Marta Fernández, Elvira Valdivielso, José Manuel |
| author2_role | author author author author author |
| author_browse | Bozic, Milica De Rooij, Johan Fernández, Elvira Parisi, Eva Ruiz Ortega, Marta Valdivielso, José Manuel |
| author_facet | Bozic, Milica De Rooij, Johan Parisi, Eva Ruiz Ortega, Marta Fernández, Elvira Valdivielso, José Manuel |
| author_role | author |
| collection | Biblos-e Archivo. Repositorio Institucional de la UAM |
| 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 |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_c4d32ff58c8aae5995d6c1eb4e57ae8d |
| institution | Universidad Autónoma de Madrid |
| instname_str | Universidad Autónoma de Madrid |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:repositorio.uam.es:10486/665338 |
| publishDate | 2011 |
| publishDateSort | 2011 |
| publisher | American Society of Nephrology |
| publisherStr | American Society of Nephrology |
| reponame_str | Biblos-e Archivo. Repositorio Institucional de la UAM |
| spelling | Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells Bozic, Milica De Rooij, Johan Parisi, Eva Ruiz Ortega, Marta Fernández, Elvira Valdivielso, José Manuel Epithelial cells Cell differentiation Actins Fibrosis Medicina 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 This 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 Nephrology http://hdl.handle.net/10486/665338 https://dx.doi.org/10.1681/ASN.2010070701 |
| spellingShingle | Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells Bozic, Milica Epithelial cells Cell differentiation Actins Fibrosis Medicina |
| title | 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_short | Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells |
| title_sort | Glutamatergic signaling maintains the epithelial phenotype of proximal tubular cells |
| topic | Epithelial cells Cell differentiation Actins Fibrosis Medicina |
| topic_facet | Epithelial cells Cell differentiation Actins Fibrosis Medicina |
| url | http://hdl.handle.net/10486/665338 https://dx.doi.org/10.1681/ASN.2010070701 |