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Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice

Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effe...

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Autores principales: Kim, Jung-Yeon, Jo, Jungmin, Kim, Kiryeong, An, Hyun-Jin, Gwon, Mi-Gyeong, Gu, Hyemin, Kim, Hyun-Ju, Yang, A Young, Kim, Sung-Woo, Jeon, Eon Ju, Park, Jae-Hyung, Leem, Jaechan, Park, Kwan-Kyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720310/
https://www.ncbi.nlm.nih.gov/pubmed/31431003
http://dx.doi.org/10.3390/antiox8080322
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author Kim, Jung-Yeon
Jo, Jungmin
Kim, Kiryeong
An, Hyun-Jin
Gwon, Mi-Gyeong
Gu, Hyemin
Kim, Hyun-Ju
Yang, A Young
Kim, Sung-Woo
Jeon, Eon Ju
Park, Jae-Hyung
Leem, Jaechan
Park, Kwan-Kyu
author_facet Kim, Jung-Yeon
Jo, Jungmin
Kim, Kiryeong
An, Hyun-Jin
Gwon, Mi-Gyeong
Gu, Hyemin
Kim, Hyun-Ju
Yang, A Young
Kim, Sung-Woo
Jeon, Eon Ju
Park, Jae-Hyung
Leem, Jaechan
Park, Kwan-Kyu
author_sort Kim, Jung-Yeon
collection PubMed
description Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effect against the disease remains unclear. In this study, we aimed to evaluate whether SRT1720, a potent and specific activator of Sirt1, could ameliorate cisplatin-induced AKI. We found that SRT1720 treatment ameliorated cisplatin-induced acute renal failure and histopathological alterations. Increased levels of tubular injury markers in kidneys were significantly attenuated by SRT1720. SRT1720 treatment also suppressed caspase-3 activation and apoptotic cell death. Increased expression of 4-hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathione/oxidized glutathione after cisplatin injection were significantly reversed by SRT1720. In addition, SRT1720 treatment decreased renal expression of pro-inflammatory cytokines and prevented macrophage infiltration into damaged kidneys. We also showed that the therapeutic effects of SRT1720 were associated with reduced acetylation of p53 and nuclear factor kappa-B p65 and preservation of peroxisome function, as evidenced by recovered expression of markers for number and function of peroxisome. These results suggest that Sirt1 activation by SRT1720 would be a useful therapeutic option for cisplatin-induced AKI.
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spelling pubmed-67203102019-10-30 Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice Kim, Jung-Yeon Jo, Jungmin Kim, Kiryeong An, Hyun-Jin Gwon, Mi-Gyeong Gu, Hyemin Kim, Hyun-Ju Yang, A Young Kim, Sung-Woo Jeon, Eon Ju Park, Jae-Hyung Leem, Jaechan Park, Kwan-Kyu Antioxidants (Basel) Article Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effect against the disease remains unclear. In this study, we aimed to evaluate whether SRT1720, a potent and specific activator of Sirt1, could ameliorate cisplatin-induced AKI. We found that SRT1720 treatment ameliorated cisplatin-induced acute renal failure and histopathological alterations. Increased levels of tubular injury markers in kidneys were significantly attenuated by SRT1720. SRT1720 treatment also suppressed caspase-3 activation and apoptotic cell death. Increased expression of 4-hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathione/oxidized glutathione after cisplatin injection were significantly reversed by SRT1720. In addition, SRT1720 treatment decreased renal expression of pro-inflammatory cytokines and prevented macrophage infiltration into damaged kidneys. We also showed that the therapeutic effects of SRT1720 were associated with reduced acetylation of p53 and nuclear factor kappa-B p65 and preservation of peroxisome function, as evidenced by recovered expression of markers for number and function of peroxisome. These results suggest that Sirt1 activation by SRT1720 would be a useful therapeutic option for cisplatin-induced AKI. MDPI 2019-08-19 /pmc/articles/PMC6720310/ /pubmed/31431003 http://dx.doi.org/10.3390/antiox8080322 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kim, Jung-Yeon
Jo, Jungmin
Kim, Kiryeong
An, Hyun-Jin
Gwon, Mi-Gyeong
Gu, Hyemin
Kim, Hyun-Ju
Yang, A Young
Kim, Sung-Woo
Jeon, Eon Ju
Park, Jae-Hyung
Leem, Jaechan
Park, Kwan-Kyu
Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice
title Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice
title_full Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice
title_fullStr Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice
title_full_unstemmed Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice
title_short Pharmacological Activation of Sirt1 Ameliorates Cisplatin-Induced Acute Kidney Injury by Suppressing Apoptosis, Oxidative Stress, and Inflammation in Mice
title_sort pharmacological activation of sirt1 ameliorates cisplatin-induced acute kidney injury by suppressing apoptosis, oxidative stress, and inflammation in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720310/
https://www.ncbi.nlm.nih.gov/pubmed/31431003
http://dx.doi.org/10.3390/antiox8080322
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