Abstract: TH-PO036
Sirt3 Modulates Fatty Acid Oxidation and Attenuates Cisplatin-Induced AKI in Mice
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, Ming, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- 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
- 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
Acute kidney injury (AKI) induced by cisplatin is very common in the clinic. Fatty acid oxidative damage is an important mechanism of renal fibrosis. Sirt3 has been shown to alleviate AKI by improving mitochondrial function and was found to be involved in the regulation of fatty acid oxidation (FAO) in other disease models. However, it is not clear whether Sirt3 is involved in regulating FAO to improve the prognosis of AKI.
Methods
Male SV129 and Sirt3 knockout (KO) mice were administered a single intraperitoneal (i.p.) injection of cisplatin (20 mg/kg) with or without treatment with honokiol (5mg/kg/day). Additionally, cultured mouse renal tubule epithelial cells (mRTECs) were treated with cisplatin (5μmol/L). Then, FAO and renal injury were evaluated.
Results
Oil red O staining and free fatty acids(FFA )analysis of kidney tissues from WT cisplatin-treated mice showed fatty acid oxidative damage and extensive lipid deposition in the mice. Metabolomics analysis revealed decreased ATP production and the presence of disordered energy metabolism. Additionally, fatty acid accumulation induced the apoptosis of mRTECs. The expression of Sirt3 was decreased in mice with cisplatin-induced AKI compared to that in control mice. Sirt3 deletion aggravated FAO dysfunction, resulting in the increased apoptosis of kidney tissues and aggravated renal injury. The activation of Sirt3 by honokiol improved FAO and renal function and reduced fatty acid deposition. In vivo and in vitro experiments confirmed that Sirt3 regulates fatty acid oxidation by deacetylating LKB1 and activating AMPK. In addition, Sirt3 increased ATP production and reduced ROS and lipid peroxidation by improving mitochondrial function.
Conclusion
These findings indicated that activated Sirt3 could protect against cisplatin-induced acute kidney injury, possibly by improving FAO and mitochondrial function, and that improving FAO in AKI may be a potential therapeutic strategy in the future.
Funding
- Government Support - Non-U.S.