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Kidney Week

Abstract: PO0332

Class IIa Histone Deacetylase Inhibition Blunts AKI by Suppressing Apoptosis, Enhancing Autophagy, and Promoting Cellular Proliferation in Mice

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Li, Jialu, Shanghai East Hospital, Shanghai, Shanghai, China
  • Yu, Chao, Shanghai East Hospital, Shanghai, Shanghai, China
  • Zhuang, Shougang, Rhode Island Hospital, Providence, Rhode Island, United States
Background

Expression and function of histone deacetylases (HDACs) vary with cell types and insults. Our recent studies have shown that class IIa HDACs contribute to renal fibrosis chronically, but their roles in acute kidney injury (AKI) remain unknown.

Methods

In this study, we examined the effect of TMP269, a potent and selective class IIa HDAC inhibitor on folic acid (FA) and ischemia/reperfusion (I/R) -induced AKI in mice.

Results

Protein levels of four class IIa HDAC isoforms (4, 5, 7, 9) were increased in the kidney of folic acid (FA) and ischemia/reperfusion (I/R)-induced AKI, with HDAC4 being more abundant. Administration of TMP269, a potent and selective class IIa HDAC inhibitor, reduced expression of HDAC4 and increased expression of acetyl-histone H3. This was coincident with improved renal function, reduced tubular injury and less apoptosis, and enhanced tubular cell proliferation. Mechanistical studies showed that TMP269 treatment inhibited FA or I/R -induced p53 acetylation and phosphorylation, as well as caspase-3 cleavage and Bax expression. In contrast, TMP269 increased expression of Bcl-2, an anti-apoptotic protein and PCNA. TMP269 was also effective in promoting cellular autophagy as indicated by increased expression of Atg7, Beclin-1 and LC3II. Moreover, class IIa HDAC inhibition resulted in the restoration of E-cadherin and upregulation of BMP7 and klotho, two renoprotective proteins.

Conclusion

These results indicated that activation of class IIa HDACs, in particular, HDAC4, contributes to AKI and renal tubular apoptosis, while targeted inhibition of class IIa HDACs protects against AKI through a mechanism associated with reduced apoptosis and enhanced autophagy and cellular regeneration.

Funding

  • Government Support – Non-U.S.