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2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury

Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Selective inhibition of HDAC6 might be a potential treatment for AKI. In our previous study, a highly selective HDAC6 inhibitor (HDAC6i) 23BB effectively protected agai...

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Autores principales: Hao, Yan, Guo, Fan, Huang, Zhuo, Feng, Yuying, Xia, Zijing, Liu, Jing, Li, Lingzhi, Huang, Rongshuang, Lin, Lin, Ma, Liang, Fu, Ping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970081/
https://www.ncbi.nlm.nih.gov/pubmed/31894849
http://dx.doi.org/10.1042/BSR20191538
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author Hao, Yan
Guo, Fan
Huang, Zhuo
Feng, Yuying
Xia, Zijing
Liu, Jing
Li, Lingzhi
Huang, Rongshuang
Lin, Lin
Ma, Liang
Fu, Ping
author_facet Hao, Yan
Guo, Fan
Huang, Zhuo
Feng, Yuying
Xia, Zijing
Liu, Jing
Li, Lingzhi
Huang, Rongshuang
Lin, Lin
Ma, Liang
Fu, Ping
author_sort Hao, Yan
collection PubMed
description Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Selective inhibition of HDAC6 might be a potential treatment for AKI. In our previous study, a highly selective HDAC6 inhibitor (HDAC6i) 23BB effectively protected against rhabdomyolysis-induced AKI with good safety. However, whether 23BB possessed favorable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by acute kidney dysfunction and pathological changes, companied by the overexpression of HDAC6 in tubular epithelial cells. Pharmacological inhibition of HDAC6 by the treatment of 23BB significantly attenuated sCr, BUN and renal tubular damage. Mechanistically, 23BB enhanced the acetylation of histone H3 to reduce the HDAC6 activity. Cisplatin-induced AKI triggered multiple signal mediators of endoplasmic reticulum (ER) stress including PERK, ATF6 and IRE1 pathway, as well as CHOP, GRP78, p-JNK and caspase 12 proteins. Oral administration of our HDAC6i 23BB at a dose of 40 mg/kg/d for 3 days notably improved above-mentioned responses in the injured kidney tissues. HDAC6 inhibition also reduced the number of TUNEL-positive tubular cells and regulated apoptosis-related protein expression. Overall, these data highlighted that HDAC6 inhibitor 23BB modulated apoptosis via the inhibition of ER stress in the tubular epithelial cells of cisplatin-induced AKI.
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spelling pubmed-69700812020-01-24 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury Hao, Yan Guo, Fan Huang, Zhuo Feng, Yuying Xia, Zijing Liu, Jing Li, Lingzhi Huang, Rongshuang Lin, Lin Ma, Liang Fu, Ping Biosci Rep Therapeutics & Molecular Medicine Histone deacetylases 6 (HDAC6) has been reported to be involved in the pathogenesis of cisplatin-induced acute kidney injury (AKI). Selective inhibition of HDAC6 might be a potential treatment for AKI. In our previous study, a highly selective HDAC6 inhibitor (HDAC6i) 23BB effectively protected against rhabdomyolysis-induced AKI with good safety. However, whether 23BB possessed favorable renoprotection against cisplatin-induced AKI and the involved mechanisms remained unknown. In the study, cisplatin-injected mice developed severe AKI symptom as indicated by acute kidney dysfunction and pathological changes, companied by the overexpression of HDAC6 in tubular epithelial cells. Pharmacological inhibition of HDAC6 by the treatment of 23BB significantly attenuated sCr, BUN and renal tubular damage. Mechanistically, 23BB enhanced the acetylation of histone H3 to reduce the HDAC6 activity. Cisplatin-induced AKI triggered multiple signal mediators of endoplasmic reticulum (ER) stress including PERK, ATF6 and IRE1 pathway, as well as CHOP, GRP78, p-JNK and caspase 12 proteins. Oral administration of our HDAC6i 23BB at a dose of 40 mg/kg/d for 3 days notably improved above-mentioned responses in the injured kidney tissues. HDAC6 inhibition also reduced the number of TUNEL-positive tubular cells and regulated apoptosis-related protein expression. Overall, these data highlighted that HDAC6 inhibitor 23BB modulated apoptosis via the inhibition of ER stress in the tubular epithelial cells of cisplatin-induced AKI. Portland Press Ltd. 2020-01-17 /pmc/articles/PMC6970081/ /pubmed/31894849 http://dx.doi.org/10.1042/BSR20191538 Text en © 2020 The Author(s). https://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
spellingShingle Therapeutics & Molecular Medicine
Hao, Yan
Guo, Fan
Huang, Zhuo
Feng, Yuying
Xia, Zijing
Liu, Jing
Li, Lingzhi
Huang, Rongshuang
Lin, Lin
Ma, Liang
Fu, Ping
2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury
title 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury
title_full 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury
title_fullStr 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury
title_full_unstemmed 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury
title_short 2-Methylquinazoline derivative 23BB as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury
title_sort 2-methylquinazoline derivative 23bb as a highly selective histone deacetylase 6 inhibitor alleviated cisplatin-induced acute kidney injury
topic Therapeutics & Molecular Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970081/
https://www.ncbi.nlm.nih.gov/pubmed/31894849
http://dx.doi.org/10.1042/BSR20191538
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