Abstract: TH-PO037
Sirtuin 3 Suppresses Ferroptosis in Cisplatin-Induced AKI
Session Information
- AKI: Mechanisms - Primary Injury and Repair - I
November 07, 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
- Li, Canming, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
- Ye, Zengchun, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
- Li, Ming, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
- Peng, Hui, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
- Lou, Tan-qi, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, GUANGDONG, China
Background
Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that protects against acute kidney injury (AKI) by mitigating renal oxidative stress. Ferroptosis, a recently characterized form of regulated cell death triggered by massive lipid peroxidation, is known to play a critical role in the pathogenesis of AKI. However, the role of SIRT3 in regulating ferroptosis in cisplatin-induced AKI (Cis-AKI) is unclear. Therefore, we aim to determine whether SIRT3 protects kidney function by restraining ferroptosis in Cis-AKI.
Methods
Male 129 wild type (WT) and SIRT3 knockout (KO) mice received cisplatin by a single intraperitoneal injection with or without Fer-1 (a ferroptosis inhibitor) and honokiol (a SIRT3 activator). AKI was determined by serum creatinine (Scr), blood urea nitrogen (BUN), and tubular damage on PAS staining 72h after cisplatin injection. Ferroptosis was assessed by multiple indicators, including the extent of lipid peroxidation (4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and glutathione/ oxidized glutathione (GSH/GSSG) ratio), and the level of glutathione peroxidase 4 (GPX4) and xCT. The expression of SIRT3 was detected by qPCR, western blot and immunohistochemistry. In addition, the status of p53 acetylation was evaluated by immunoprecipitation.
Results
Both WT and SIRT3 KO mice developed AKI after cisplatin injection. In response to cisplatin treatment, sirt3 expression levels were markedly decreased. In AKI groups, kidney function (Scr and BUN) and tubular damage extent on PAS staining were more severe when SIRT3 was missing. Ferroptosis indicators, including the increased levels of 4-HNE and MDA, the reduced ratio of GSH/GSSG, and the decreased expression of GPX4 and xCT, were also had more significant changes in SIRT3 KO mice than in the WT mice after cisplatin treatment. In contrast, honokiol protects against Cis-AKI as demonstrated by improved renal dysfunction, attenuated renal pathological changes, and decreased ferroptosis. In addition, Fer-1 exhibited protection against AKI in WT mice, but not in SIRT3 KO mice. Mechanistic studies demonstrated that cisplatin treatment induced p53 acetylation, and the acetylation of p53 in SIRT3 KO mice was more pronounced than in WT mice.
Conclusion
These data indicate that ferroptosis might be modulated by SIRT3 through p53 acetylation and suggest that ferroptosis is an important death mechanism in Cis-AKI.
Funding
- Government Support - Non-U.S.