Histone deacetylase inhibitors protect against cisplatin-induced acute kidney injury by activating autophagy in proximal tubular cells

Cell Death & Disease
Jing LiuZheng Dong

Abstract

Histone deacetylase inhibitors (HDACi) have therapeutic effects in models of various renal diseases including acute kidney injury (AKI); however, the underlying mechanism remains unclear. Here we demonstrate that two widely tested HDACi (suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA)) protect the kidneys in cisplatin-induced AKI by enhancing autophagy. In cultured renal proximal tubular cells, SAHA and TSA enhanced autophagy during cisplatin treatment. We further verified the protective effect of TSA against cisplatin-induced apoptosis in these cells. Notably, inhibition of autophagy by chloroquine or by autophagy gene 7 (Atg7) ablation diminished the protective effect of TSA. In mice, TSA increased autophagy in renal proximal tubules and protected against cisplatin-induced AKI. The in vivo effect of TSA was also abolished by chloroquine and by Atg7 knockout specifically from renal proximal tubules. Mechanistically, TSA stimulated AMPK and inactivated mTOR during cisplatin treatment of proximal tubule cells and kidneys in mice. Together, these results suggest that HDACi may protect kidneys by activating autophagy in proximal tubular cells.

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Citations

Jun 14, 2018·Annals of Medicine·Mingjuan YanZheng Dong
Jul 27, 2018·The Journal of Pharmacy and Pharmacology·Hepeng WangKexin Liu
Feb 28, 2019·American Journal of Physiology. Renal Physiology·Kelly A HyndmanSureena Monteiro-Pai
Mar 19, 2019·Circulation. Arrhythmia and Electrophysiology·Beatrix ScholzFrank Ulrich Müller
Apr 18, 2019·Journal of Cellular and Molecular Medicine·Meiling ZhengZheng Dong
Apr 18, 2019·American Journal of Physiology. Renal Physiology·Wei CaoChangying Xing
Mar 27, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wei DuJun Hao
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Jan 18, 2019·Nature Reviews. Nephrology·Chunyuan GuoZheng Dong
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Sep 19, 2019·American Journal of Physiology. Renal Physiology·Ying FuZheng Dong
Jan 31, 2020·Cell Death & Disease·Zhaoxin HuWei Zhang
Aug 28, 2019·Canadian Journal of Kidney Health and Disease·Samuel A Silver, Casimiro Gerarduzzi
Apr 19, 2020·Seminars in Nephrology·Kelly A Hyndman
Feb 23, 2021·American Journal of Physiology. Renal Physiology·Fei DengYashpal S Kanwar
Jun 3, 2021·Pharmaceuticals·Pía LorenLuis A Salazar
Jul 6, 2021·Frontiers in Pharmacology·Xun ZhouNa Liu
Oct 13, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Lulu KongShaohua Wei

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Methods Mentioned

BETA
fluorescence microscopy
transfection
transgenic
confocal microscopy
transfecting
Protein Assay
electrophoresis

Software Mentioned

ImageJ
GraphPad Prism

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