Abstract: SA-PO093
3-Deazaneplanocin A Protects Against Cisplatin-Induced Tubular Cell Apoptosis and AKI by Restoration of E-Cadherin Expression
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Ni, Jun, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Ying, Hou Xi, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
- Wang, Xueqiao, Tongji University, Shanghai, China
- Shi, Yingfeng, Shanghai Dongfang Hospital, Shanghai, China
- Xu, Liuqing, Tongji University, Shanghai, China
- Liu, Na, Shanghai East Hospital, Shanghai, China
- Qiu, Andong, Tongji University, Shanghai, China
- Zhuang, Shougang, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, United States
Background
3-deazaneplanocin A (DZNeP) has been used as an inhibitor of enhancer of zeste homolog 2 (EZH2). Here, we explore the role and underlying mechanisms of 3-DZNeP in cisplatin nephrotoxicity.
Methods
Cultured mouse renal proximal tubular epithelial cells (mTECs) were exposed to cisplatin in the presence or absence of EZH2 inhibitors (3-DZNeP, miRNA). A murine model of cisplatin-induced acute kidney injury was used to examine the effect of 3-DZNeP on cisplatin nephrotoxicity.
Results
Exposure of cultured mTECs to cisplatin resulted in dose and time-dependent cleavage of caspase-3, decrease of cell viability and increase of histone H3 lysine 27 trimethylation (H3K27me3), whereas expression levels of EZH2, a major methyltransferase of H3K27me3, were not affected. Treatment with 3-DZNeP significantly inhibited cisplatin-induced activation of caspase-3, apoptosis, loss of cell viability but did not alter EZH2 expression and H3K27me3 levels. Similarly, administration of 3-DZNeP also attenuated cisplatin-induced renal dysfunction, morphological damage and renal tubular cell death in a mouse model. Mechanistically, 3-DZNeP treatment did not affect activation of extracellular signal-regulated kinase 1/2, p38 or c-Jun N-terminal kinases 1/2, which contribute to renal epithelial cell death, but caused dose-dependent restoration of E-cadherin in mTECs exposed to cisplatin. Silencing of E-cadherin expression by siRNA abolished the cytoprotective effects 3-DZNeP. In contrast, 3-DZNeP treatment potentiated the cytotoxic effect of cisplatin in H1299, a non-small cell lung cancer cell line that expresses lower E-cadherin level.
Conclusion
These data indicate that 3-DZNeP can suppress cisplatin-induced tubular epithelial cell apoptosis and acute kidney injury via an E-cadherin dependent mechanism and suggest that combined application of 3-DZNeP with cisplatin is a novel chemotherapeutic strategy that enhances the anti-tumor effect of cisplatin and reduces its nephrotoxicity.
Funding
- Government Support - Non-U.S.