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4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression

Different forms of acute kidney injury (AKI) have been associated with endoplasmic reticulum (ER) stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI....

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Autores principales: Carlisle, Rachel E., Brimble, Elise, Werner, Kaitlyn E., Cruz, Gaile L., Ask, Kjetil, Ingram, Alistair J., Dickhout, Jeffrey G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885586/
https://www.ncbi.nlm.nih.gov/pubmed/24416259
http://dx.doi.org/10.1371/journal.pone.0084663
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author Carlisle, Rachel E.
Brimble, Elise
Werner, Kaitlyn E.
Cruz, Gaile L.
Ask, Kjetil
Ingram, Alistair J.
Dickhout, Jeffrey G.
author_facet Carlisle, Rachel E.
Brimble, Elise
Werner, Kaitlyn E.
Cruz, Gaile L.
Ask, Kjetil
Ingram, Alistair J.
Dickhout, Jeffrey G.
author_sort Carlisle, Rachel E.
collection PubMed
description Different forms of acute kidney injury (AKI) have been associated with endoplasmic reticulum (ER) stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI. 4-phenylbutyrate (4-PBA) is an FDA approved substance used in children who suffer from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding at the molecular level and preventing misfolded protein aggregation. The main objective of this study was to determine if 4-PBA could protect from AKI induced by ER stress, as typified by the TM-model, and what mechanism(s) of 4-PBA's action were responsible for protection. C57BL/6 mice were treated with saline, TM or TM plus 4-PBA. 4-PBA partially protected the anatomic segment most susceptible to damage, the outer medullary stripe, from TM-induced AKI. In vitro work showed that 4-PBA protected human proximal tubular cells from apoptosis and TM-induced CHOP expression, an ER stress inducible proapoptotic gene. Further, immunofluorescent staining in the animal model found similar protection by 4-PBA from CHOP nuclear translocation in the tubular epithelium of the medulla. This was accompanied by a reduction in apoptosis and GRP78 expression. CHOP(−/−) mice were protected from TM-induced AKI. The protective effects of 4-PBA extended to the ultrastructural integrity of proximal tubule cells in the outer medulla. When taken together, these results indicate that 4-PBA acts as an ER stress inhibitor, to partially protect the kidney from TM-induced AKI through the repression of ER stress-induced CHOP expression.
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spelling pubmed-38855862014-01-10 4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression Carlisle, Rachel E. Brimble, Elise Werner, Kaitlyn E. Cruz, Gaile L. Ask, Kjetil Ingram, Alistair J. Dickhout, Jeffrey G. PLoS One Research Article Different forms of acute kidney injury (AKI) have been associated with endoplasmic reticulum (ER) stress; these include AKI caused by acetaminophen, antibiotics, cisplatin, and radiocontrast. Tunicamycin (TM) is a nucleoside antibiotic known to induce ER stress and is a commonly used inducer of AKI. 4-phenylbutyrate (4-PBA) is an FDA approved substance used in children who suffer from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding at the molecular level and preventing misfolded protein aggregation. The main objective of this study was to determine if 4-PBA could protect from AKI induced by ER stress, as typified by the TM-model, and what mechanism(s) of 4-PBA's action were responsible for protection. C57BL/6 mice were treated with saline, TM or TM plus 4-PBA. 4-PBA partially protected the anatomic segment most susceptible to damage, the outer medullary stripe, from TM-induced AKI. In vitro work showed that 4-PBA protected human proximal tubular cells from apoptosis and TM-induced CHOP expression, an ER stress inducible proapoptotic gene. Further, immunofluorescent staining in the animal model found similar protection by 4-PBA from CHOP nuclear translocation in the tubular epithelium of the medulla. This was accompanied by a reduction in apoptosis and GRP78 expression. CHOP(−/−) mice were protected from TM-induced AKI. The protective effects of 4-PBA extended to the ultrastructural integrity of proximal tubule cells in the outer medulla. When taken together, these results indicate that 4-PBA acts as an ER stress inhibitor, to partially protect the kidney from TM-induced AKI through the repression of ER stress-induced CHOP expression. Public Library of Science 2014-01-08 /pmc/articles/PMC3885586/ /pubmed/24416259 http://dx.doi.org/10.1371/journal.pone.0084663 Text en © 2014 Carlisle et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Carlisle, Rachel E.
Brimble, Elise
Werner, Kaitlyn E.
Cruz, Gaile L.
Ask, Kjetil
Ingram, Alistair J.
Dickhout, Jeffrey G.
4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression
title 4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression
title_full 4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression
title_fullStr 4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression
title_full_unstemmed 4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression
title_short 4-Phenylbutyrate Inhibits Tunicamycin-Induced Acute Kidney Injury via CHOP/GADD153 Repression
title_sort 4-phenylbutyrate inhibits tunicamycin-induced acute kidney injury via chop/gadd153 repression
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885586/
https://www.ncbi.nlm.nih.gov/pubmed/24416259
http://dx.doi.org/10.1371/journal.pone.0084663
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