Histone deacetylase 6 (HDAC6) has been shown to be involved in various pathological conditions, including cancer, neurodegenerative disorders and inflammatory diseases. Nonetheless, its specific role in drug-induced nephrotoxicity is poorly understood. Cisplatin (dichlorodiamino platinum) belongs to an inorganic platinum – fundamental chemotherapeutic drug utilized in the therapy of various solid malignant tumors. However, the use of cisplatin is extremely limited by obvious side effects, for instance bone marrow suppression and nephrotoxicity. In the present study, we utilized a murine model of cisplatin-induced acute kidney injury (AKI) and a highly selective inhibitor of HDAC6, tubastatin A (TA), to assess the role of HDAC6 in nephrotoxicity and its associated mechanisms. Cisplatin-induced AKI was accompanied by increased expression and activation of HDAC6; blocking HDAC6 with TA lessened renal dysfunction, attenuated renal pathological changes, reduced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule 1, and decreased tubular cell apoptosis. In cultured human epithelial cells, TA or HDAC6 siRNA treatment also inhibited cisplatin-induced apoptosis. Mechanistic studies demonstrated that cisplatin treatment induced phosphorylation of AKT and loss of E-cadherin in the nephrotoxic kidney, and administration of TA enhanced AKT phosphorylation and preserved E-cadherin expression. HDAC6 inhibition also potentiated autophagy as evidenced by increased expression of autophagy-related gene (Atg) 7 (Atg7), Beclin-1, and decreased renal oxidative stress as demonstrated by up-regulation of superoxide dismutase (SOD) activity and down-regulation of malondialdehyde levels. Moreover, TA was effective in inhibiting nuclear factor-κ B (NF-κB) phosphorylation and suppressing the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Collectively, these data provide strong evidence that HDAC6 inhibition is protective against cisplatin-induced AKI and suggest that HDAC6 may be a potential therapeutic target for AKI treatment.
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A representative image of an airway from a mouse sensitized and challenged with an allergen. The histological image was captured 24 hours after allergen exposure at which point airway hyperresponsiveness persists without any discernible change to wall structure. In Clinical Science volume 132, issue 3, Wang et al. report on the effects of airway remodelling and allergy on airway responsiveness; for details see pages 327–338. Image kindly provided by Kimberley C.W. Wang (The University of Western Australia).
Research Article|
February 02 2018
Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury
Jinhua Tang;
Jinhua Tang
*
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Yingfeng Shi;
Yingfeng Shi
*
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Na Liu;
Na Liu
*
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Correspondence: Shougang Zhuang ([email protected]) or Na Liu ([email protected])
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Liuqing Xu;
Liuqing Xu
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Xiujuan Zang;
Xiujuan Zang
2Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, China
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Peibin Li;
Peibin Li
3Department of Nephrology, Dayao People’s Hospital, Chuxiong, Yun Nan province, China
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Juanlian Zhang;
Juanlian Zhang
4School of Life Science and Technology, Tongji University, Shanghai, China
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Xiaoqing Zheng;
Xiaoqing Zheng
4School of Life Science and Technology, Tongji University, Shanghai, China
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Andong Qiu;
Andong Qiu
5School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China
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Shougang Zhuang
1Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
6Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI, U.S.A.
Correspondence: Shougang Zhuang ([email protected]) or Na Liu ([email protected])
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Publisher: Portland Press Ltd
Received:
October 05 2017
Revision Received:
January 04 2018
Accepted:
January 22 2018
Accepted Manuscript online:
January 22 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (3): 339–359.
Article history
Received:
October 05 2017
Revision Received:
January 04 2018
Accepted:
January 22 2018
Accepted Manuscript online:
January 22 2018
Citation
Jinhua Tang, Yingfeng Shi, Na Liu, Liuqing Xu, Xiujuan Zang, Peibin Li, Juanlian Zhang, Xiaoqing Zheng, Andong Qiu, Shougang Zhuang; Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury. Clin Sci (Lond) 14 February 2018; 132 (3): 339–359. doi: https://doi.org/10.1042/CS20171417
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