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Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury.

Authors
  • Tang, Jinhua1
  • Shi, Yingfeng1
  • Liu, Na2
  • Xu, Liuqing1
  • Zang, Xiujuan3
  • Li, Peibin4
  • Zhang, Juanlian5
  • Zheng, Xiaoqing5
  • Qiu, Andong6
  • Zhuang, Shougang2, 7
  • 1 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. , (China)
  • 2 Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China [email protected] [email protected] , (China)
  • 3 Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, China. , (China)
  • 4 Department of Nephrology, Dayao People's Hospital, Chuxiong, Yun Nan province, China. , (China)
  • 5 School of Life Science and Technology, Tongji University, Shanghai, China. , (China)
  • 6 School of Life Science and Technology, Advanced Institute of Translational Medicine, Tongji University, Shanghai, China. , (China)
  • 7 Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI, U.S.A.
Type
Published Article
Journal
Clinical Science
Publisher
Portland Press
Publication Date
Feb 14, 2018
Volume
132
Issue
3
Pages
339–359
Identifiers
DOI: 10.1042/CS20171417
PMID: 29358506
Source
Medline
Keywords
License
Unknown

Abstract

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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