Abstract: TH-PO110
SIRT2 Regulates Cisplatin-Induced Endoplasmic Reticulum Stress Through Heat Shock Factor 1 Deacetylation
Session Information
- AKI: Mechanisms - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Park, Woong, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
- Jung, Yujin, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
- Kim, Hyeongwan, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
- Yeom, Jihyun, Jeonbuk National University Hospital, Jeonju, Jeollabuk-do , Korea (the Republic of)
- Lee, Soo jin, Jeonbuk National University Hospital, Jeonju, Jeollabuk-do , Korea (the Republic of)
- Shin, Yujin, Jeonbuk National University Hospital, Jeonju, Jeollabuk-do , Korea (the Republic of)
- Kim, Won, Jeonbuk National University Medical School, Jeonju, Jeollabuk-do , Korea (the Republic of)
Background
Nephrotoxicity is an important cisplatin-induced adverse reaction and restricts the use of cisplatin to treat malignant tumors. Endoplasmic reticulum (ER) stress is caused by the accumulation of misfolded proteins, and can be induced by cisplatin in the kidney. SIRT2, a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, is a member of the sirtuin family. In this study, we evaluated role of SIRT2 in cisplatin-induced ER stress.
Methods
To investigate the effect of SIRT2 on cisplatin-induced ER stress, we used SIRT2 knockout mice and human proximal tubular epithelial cells (HK-2 cells). We treated HK-2 cells with cisplatin (20 µg/mL) and administered cisplatin (20 mg/kg, i.p.) to mice to induce acute kidney injury. We evaluated the changes of ER stress and its signal mechanism.
Results
In vivo experiment, cisplatin administration was found to significantly increase the expressions of PRKR-like ER kinase (PERK), phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), and the C/EBP homologous protein (CHOP) and caspase-12 in the kidneys of SIRT2-wild type mice. However, cisplatin-induced increases in the expressions of p-PERK, p-eIF2α, CHOP and, caspase-12 were diminished in kidneys of SIRT2 knockout mice. In vitro, cisplatin significantly increased the expressions of p-PERK, p-eIF2α, CHOP, and caspase-12 in HK-2 cells. When the effect of SIRT2 on cisplatin-induced ER stress was evaluated using SIRT2-siRNA (ON-TARGET plus human SIRT2 siRNA) or the SIRT2 inhibitors, AGK2 and AK1, knockdown or inhibition of SIRT2 significantly attenuated the cisplatin-induced protein expression of p-PERK, p-eIF2α, CHOP, and caspase-12. Immunoprecipitation studies showed SIRT2 bound physically to heat shock factor (HSF)1 and that HSF1 acetylation was significantly increased by cisplatin. In addition, knockdown of SIRT2 increased cisplatin-induced HSF1 acetylation and increased the expression of heat shock protein (HSP)70.
Conclusion
These observations suggest that suppression of SIRT2 ameliorates cisplatin-induced ER stress by increasing HSF1 acetylation and HSP expression.
Funding
- Government Support – Non-U.S.