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Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells

Acute kidney injury (AKI) is characterized by tubular cell death and interstitial inflammation. TWEAK promotes experimental kidney injury and activates the transcription factor NF-κB, a key regulator of genes involved in cell survival and inflammatory response. In search of potential therapeutic tar...

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Autores principales: Poveda, Jonay, Sanz, Ana B, Carrasco, Susana, Ruiz-Ortega, Marta, Cannata-Ortiz, Pablo, Sanchez-Niño, Maria D, Ortiz, Alberto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565957/
https://www.ncbi.nlm.nih.gov/pubmed/28684863
http://dx.doi.org/10.1038/emm.2017.89
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author Poveda, Jonay
Sanz, Ana B
Carrasco, Susana
Ruiz-Ortega, Marta
Cannata-Ortiz, Pablo
Sanchez-Niño, Maria D
Ortiz, Alberto
author_facet Poveda, Jonay
Sanz, Ana B
Carrasco, Susana
Ruiz-Ortega, Marta
Cannata-Ortiz, Pablo
Sanchez-Niño, Maria D
Ortiz, Alberto
author_sort Poveda, Jonay
collection PubMed
description Acute kidney injury (AKI) is characterized by tubular cell death and interstitial inflammation. TWEAK promotes experimental kidney injury and activates the transcription factor NF-κB, a key regulator of genes involved in cell survival and inflammatory response. In search of potential therapeutic targets for AKI, we compared a transcriptomics database of NF-κB-related genes from murine AKI-kidneys with a transcriptomics database of TWEAK-stimulated cultured tubular cells. Four out of twenty-four (17%) genes were significantly upregulated (false discovery rate, FDR<0.05), while nine out of twenty-four (37%) genes were significantly upregulated at FDR <0.1 in both databases. Bcl3 was the top upregulated NF-κB-related gene in experimental AKI and one of the most upregulated genes in TWEAK-stimulated tubular cells. Quantitative reverse transcription PCR (qRT-PCR), western blot and immunohistochemistry confirmed Bcl3 upregulation in both experimental conditions and localized increased Bcl3 expression to tubular cells in AKI. Transcriptomics database analysis revealed increased Bcl3 expression in numerous experimental and human kidney conditions. Furthermore, systemic TWEAK administration increased kidney Bcl3 expression. In cultured tubular cells, targeting Bcl3 by siRNA resulted in the magnification of TWEAK-induced NF-κB transcriptional activity, chemokine upregulation and Klotho downregulation, and in the sensitization to cell death induced by TWEAK/TNFα/interferon-γ. In contrast, Bcl3 overexpression decreased NF-κB transcriptional activity, inflammatory response and cell death while dampening the decrease in Klotho expression. In conclusion, Bcl3 expressed in response to TWEAK stimulation decreases TWEAK-induced inflammatory and lethal responses. Therefore, therapeutic upregulation of Bcl3 activity should be explored in kidney disease because it has advantages over chemical inhibitors of NF-κB that are known to prevent inflammatory responses but can also sensitize the cells to apoptosis.
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spelling pubmed-55659572017-08-24 Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells Poveda, Jonay Sanz, Ana B Carrasco, Susana Ruiz-Ortega, Marta Cannata-Ortiz, Pablo Sanchez-Niño, Maria D Ortiz, Alberto Exp Mol Med Original Article Acute kidney injury (AKI) is characterized by tubular cell death and interstitial inflammation. TWEAK promotes experimental kidney injury and activates the transcription factor NF-κB, a key regulator of genes involved in cell survival and inflammatory response. In search of potential therapeutic targets for AKI, we compared a transcriptomics database of NF-κB-related genes from murine AKI-kidneys with a transcriptomics database of TWEAK-stimulated cultured tubular cells. Four out of twenty-four (17%) genes were significantly upregulated (false discovery rate, FDR<0.05), while nine out of twenty-four (37%) genes were significantly upregulated at FDR <0.1 in both databases. Bcl3 was the top upregulated NF-κB-related gene in experimental AKI and one of the most upregulated genes in TWEAK-stimulated tubular cells. Quantitative reverse transcription PCR (qRT-PCR), western blot and immunohistochemistry confirmed Bcl3 upregulation in both experimental conditions and localized increased Bcl3 expression to tubular cells in AKI. Transcriptomics database analysis revealed increased Bcl3 expression in numerous experimental and human kidney conditions. Furthermore, systemic TWEAK administration increased kidney Bcl3 expression. In cultured tubular cells, targeting Bcl3 by siRNA resulted in the magnification of TWEAK-induced NF-κB transcriptional activity, chemokine upregulation and Klotho downregulation, and in the sensitization to cell death induced by TWEAK/TNFα/interferon-γ. In contrast, Bcl3 overexpression decreased NF-κB transcriptional activity, inflammatory response and cell death while dampening the decrease in Klotho expression. In conclusion, Bcl3 expressed in response to TWEAK stimulation decreases TWEAK-induced inflammatory and lethal responses. Therefore, therapeutic upregulation of Bcl3 activity should be explored in kidney disease because it has advantages over chemical inhibitors of NF-κB that are known to prevent inflammatory responses but can also sensitize the cells to apoptosis. Nature Publishing Group 2017-07 2017-07-07 /pmc/articles/PMC5565957/ /pubmed/28684863 http://dx.doi.org/10.1038/emm.2017.89 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Article
Poveda, Jonay
Sanz, Ana B
Carrasco, Susana
Ruiz-Ortega, Marta
Cannata-Ortiz, Pablo
Sanchez-Niño, Maria D
Ortiz, Alberto
Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells
title Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells
title_full Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells
title_fullStr Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells
title_full_unstemmed Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells
title_short Bcl3: a regulator of NF-κB inducible by TWEAK in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells
title_sort bcl3: a regulator of nf-κb inducible by tweak in acute kidney injury with anti-inflammatory and antiapoptotic properties in tubular cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5565957/
https://www.ncbi.nlm.nih.gov/pubmed/28684863
http://dx.doi.org/10.1038/emm.2017.89
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