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Abstract: SA-PO079

HDAC3 Contributes to Necrotic Tubular Damage in Ischemic AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Dong, Guie, Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
  • Dong, Zheng, Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, United States
Background

Histone deacetylases (HDAC) are group of enzymes that remove acetyl groups from lysine residues of histone and nonhistone proteins. The action of histone deacetylation condenses chromatin and DNA structure, resulting in the repression of gene transcription and expression. We reported that HDAC inhibitors attenuate apoptosis of renal proximal tubular cells during cisplatin treatment. This study was designed to determine the specific role of HDAC3 in acute kidney injury (AKI).

Methods

In vivo, we generated proximal tubule-specific HDAC3 knockout (PT-HDAC3-ko) mice, which were subjected to 30mins of ischemia with 48hrs of reperfusion. We also tested the effect of RGFP966, a specific pharmacological inhibitor of HDAC3. Serum sample was collected to check blood urea nitrogen (BUN) and serum creatinine. Kidney tissue was collected for histology, immunohistochemistry and immunoblot analysis. In vitro, rat proximal tubular cells (RPTC) were treated with azide for 4.5hrs followed by 2hr reperfusion to induce necrotic cell death to examine the effects of RGFP966. Necrosis was indicated by propidium iodide staining and LDH release. In addition, the effect of HDAC3 knockdown was examined.

Results

HDAC3 was localized in the nucleus and cytoplasm of proximal tubular cells in kidneys. After ischemic AKI, HDAC3 was induced. Compared to wild-type mice, PT-HDAC3-ko mice showed less ischemic AKI as indicated by less necrotic damage in proximal tubules and improved renal function with lower levels of BUN and serum creatinine. Consistently, RGFP 966 protected against ischemic AKI in mice. In immunoblot analysis, acetylation of histone H3, H2B and H4 was better preserved in kidney tissues of PT-HDAC3-ko mice. In RPTC cells, HDAC3 was induced during azide treatment and significantly increased during subsequent recovery. Both RGFP966 and HDAC3 knockdown suppressed HDAC3 induction and preserved the acetylation of histone H3, H2B and H4. Notably, both RGFP966 and HDAC3 knockdown suppressed necrosis following azide treatment.

Conclusion

HDAC3 is induced during ischemic AKI and plays an important role in necrotic damage in proximal tubules. Specific blockade of HDAC3 may have therapeutic potential in AKI.

Funding

  • NIDDK Support