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DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity

Cisplatin is a commonly used chemotherapeutic agent to treat a wide array of cancers that is frequently associated with toxic injury to the kidney due to oxidative DNA damage and perturbations in cell cycle progression leading to cell death. In this study, we investigated whether thyroid receptor in...

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Autores principales: Hama, Taketsugu, Nagesh, Prashanth K.B., Chowdhury, Pallabita, Moore, Bob M., Yallapu, Murali M., Regner, Kevin R., Park, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663775/
https://www.ncbi.nlm.nih.gov/pubmed/34806647
http://dx.doi.org/10.1172/jci.insight.139092
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author Hama, Taketsugu
Nagesh, Prashanth K.B.
Chowdhury, Pallabita
Moore, Bob M.
Yallapu, Murali M.
Regner, Kevin R.
Park, Frank
author_facet Hama, Taketsugu
Nagesh, Prashanth K.B.
Chowdhury, Pallabita
Moore, Bob M.
Yallapu, Murali M.
Regner, Kevin R.
Park, Frank
author_sort Hama, Taketsugu
collection PubMed
description Cisplatin is a commonly used chemotherapeutic agent to treat a wide array of cancers that is frequently associated with toxic injury to the kidney due to oxidative DNA damage and perturbations in cell cycle progression leading to cell death. In this study, we investigated whether thyroid receptor interacting protein 13 (TRIP13) plays a central role in the protection of the tubular epithelia following cisplatin treatment by circumventing DNA damage. Following cisplatin treatment, double-stranded DNA repair pathways were inhibited using selective blockers to proteins involved in either homologous recombination or non-homologous end joining. This led to increased blood markers of acute kidney injury (AKI) (creatinine and neutrophil gelatinase–associated lipocalin), tubular damage, activation of DNA damage marker (γ-H2AX), elevated appearance of G2/M blockade (phosphorylated histone H3 Ser10 and cyclin B1), and apoptosis (cleaved caspase-3). Conditional proximal tubule–expressing Trip13 mice were observed to be virtually protected from the cisplatin nephrotoxicity by restoring most of the pathological phenotypes back toward normal conditions. Our findings suggest that TRIP13 could circumvent DNA damage in the proximal tubules during cisplatin injury and that TRIP13 may constitute a new therapeutic target in protecting the kidney from nephrotoxicants and reduce outcomes leading to AKI.
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spelling pubmed-86637752021-12-15 DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity Hama, Taketsugu Nagesh, Prashanth K.B. Chowdhury, Pallabita Moore, Bob M. Yallapu, Murali M. Regner, Kevin R. Park, Frank JCI Insight Research Article Cisplatin is a commonly used chemotherapeutic agent to treat a wide array of cancers that is frequently associated with toxic injury to the kidney due to oxidative DNA damage and perturbations in cell cycle progression leading to cell death. In this study, we investigated whether thyroid receptor interacting protein 13 (TRIP13) plays a central role in the protection of the tubular epithelia following cisplatin treatment by circumventing DNA damage. Following cisplatin treatment, double-stranded DNA repair pathways were inhibited using selective blockers to proteins involved in either homologous recombination or non-homologous end joining. This led to increased blood markers of acute kidney injury (AKI) (creatinine and neutrophil gelatinase–associated lipocalin), tubular damage, activation of DNA damage marker (γ-H2AX), elevated appearance of G2/M blockade (phosphorylated histone H3 Ser10 and cyclin B1), and apoptosis (cleaved caspase-3). Conditional proximal tubule–expressing Trip13 mice were observed to be virtually protected from the cisplatin nephrotoxicity by restoring most of the pathological phenotypes back toward normal conditions. Our findings suggest that TRIP13 could circumvent DNA damage in the proximal tubules during cisplatin injury and that TRIP13 may constitute a new therapeutic target in protecting the kidney from nephrotoxicants and reduce outcomes leading to AKI. American Society for Clinical Investigation 2021-11-22 /pmc/articles/PMC8663775/ /pubmed/34806647 http://dx.doi.org/10.1172/jci.insight.139092 Text en © 2021 Hama et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Hama, Taketsugu
Nagesh, Prashanth K.B.
Chowdhury, Pallabita
Moore, Bob M.
Yallapu, Murali M.
Regner, Kevin R.
Park, Frank
DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
title DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
title_full DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
title_fullStr DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
title_full_unstemmed DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
title_short DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity
title_sort dna damage is overcome by trip13 overexpression during cisplatin nephrotoxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663775/
https://www.ncbi.nlm.nih.gov/pubmed/34806647
http://dx.doi.org/10.1172/jci.insight.139092
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