HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

Lang Shi; Zhixia Song; Chenglong Li; Fangjing Deng; Yao Xia; Jing Huang; Xiongfei Wu; Jiefu Zhu

doi:10.3390/cells11243951

HDAC6 Inhibition Alleviates Ischemia- and Cisplatin-Induced Acute Kidney Injury by Promoting Autophagy

Cells. 2022 Dec 7;11(24):3951. doi: 10.3390/cells11243951.

Authors

Lang Shi¹, Zhixia Song², Chenglong Li³, Fangjing Deng¹, Yao Xia², Jing Huang¹, Xiongfei Wu¹, Jiefu Zhu⁴

Affiliations

¹ Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430064, China.
² Department of Nephrology, The First Clinical Medical College of Three Gorges University, Center People's Hospital of Yichang, Yichang 443000, China.
³ Department of Urology, Renmin Hospital of Wuhan University, Wuhan 430064, China.
⁴ Department of Organ Transplantation, Renmin Hospital of Wuhan University, Wuhan 430064, China.

Abstract

Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in renal disorders, including UUO-induced fibrotic kidneys and rhabdomyolysis-induced nephropathy. However, the role of HDAC6 in ischemic acute kidney injury (AKI) and the mechanism by which HDAC6 inhibition protects tubular cells after AKI remain unclear. In the present study, we observed that HDAC6 was markedly activated in kidneys subjected to ischemia- and cisplatin (cis)-induced AKI treatment. Pharmacological inhibition of HDAC6 alleviated renal impairment and renal tubular damage after ischemia and cisplatin treatment. HDAC6 dysfunction was associated with decreased acetylation of α-tubulin at the residue of lysine 40 and autophagy. HDAC6 inhibition preserved acetyl-α-tubulin-enhanced autophagy flux in AKI and cultured tubular cells. Genetic ablation of the renal tubular (RT) Atg7 gene or pharmacological inhibition of autophagy suppressed the protective effects of HDAC6. Taken together, our study indicates that HDAC6 contributes to ischemia- and cisplatin-induced AKI by inhibiting autophagy and the acetylation of α-tubulin. These results suggest that HDAC6 could be a potential target for ischemic and nephrotoxic AKI.

Keywords: HDAC6; acute kidney injury; autophagy; cisplatin; renal ischemia/reperfusion.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute Kidney Injury* / genetics
Acute Kidney Injury* / metabolism
Autophagy / genetics
Cisplatin* / adverse effects
Histone Deacetylase 6* / genetics
Histone Deacetylase 6* / metabolism
Humans
Ischemia* / genetics
Ischemia* / metabolism
Tubulin / metabolism

Substances

Cisplatin
HDAC6 protein, human
Histone Deacetylase 6
Tubulin

Grants and funding

This research was funded by the National Youth Science Foundation of China, grant number 82100803, and the APC was funded by the Natural Science Foundation of Hubei Province (grant number 2021CFB101).