Abstract: TH-PO250

Histone Deacetylase 6 Inhibition Protects Against Cisplatin-Induced AKI

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Shi, Yingfeng, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
  • Liu, Na, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
  • Xu, Liuqing, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai , China
  • Tang, Jinhua, Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
  • Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
Background

The function of histone deacetylase 6 (HDAC6) has been demonstrated in various pathophysiological events, including cancer, neurodegenerative disorders and inflammatory diseases. Its role in cisplatin-induced acute kidney injury (AKI) is still unclear.

Methods

We used a murine model to investigate the role and mechanism of HDAC6 in cisplatin-induced AKI.

Results

HDAC6 expression levels were markedly increased in the kidneys of cisplatin-treated mice. Blocking HDAC6 activity with tubastatin A (TA), a high selective inhibitor, protects against cisplatin-induced AKI as demonstrated by improved renal dysfunction, attenuated renal pathological changes, reduced expression of AKI biomarkers (NGAL and Kim-1), and decreased tubular cell apoptosis. Administration of TA also enhanced tubular cell dedifferentiation and regeneration as evidenced by increased expression of Pax2 and proliferating cell nuclear antigen protein in the injured kidney. In vitro studies demonstrated that TA increased acetylation of histone H3 and a-tubulin and decreased cell apoptosis in cultured human proximal tubular cells. Mechanistic studies demonstrated that TA treatment enhanced AKT phosphorylation and induced autophagy. Moreover, HDAC6 blockage restrained renal oxidative stress by raising superoxide dismutase activity and lessening malondialdehyde level. Finally, TA treatment inhibited NF-κB phosphorylation as well as expression of multiple cytokines/chemokines, thereby reducing macrophage infiltration in the injured kidney.

Conclusion

These data provide strong evidence that HDAC6 inhibition protects against cisplatin-induced AKI and suggest HDAC6 as a potential therapeutic target for AKI treatment.

Funding

  • Government Support - Non-U.S.