Abstract: TH-PO336

Role of Sirt2 in a Murine Cisplatin Induced AKI Model

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Park, Woong, Chonbuk National University Medical School, Jeonju, Korea (the Republic of)
  • Jung, Yujin, chonbuk national university medical school, Jeonju, Korea (the Republic of)
  • Kim, Won, Chobuk National Univeristy Medical School, Jeonju, Korea (the Republic of)
  • Kang, Kyung Pyo, Chonbuk National University Medical School, Jeonju, Korea (the Republic of)
Background

Cisplatin based chemotherapy is commonly used in therapeutic strategies for solid tumor. However, limitation of this agent is adverse effect on normal tissue such as kidney, ear, and peripheral nerves. Mechanisms of cisplatin nephrotoxicity are proposed as oxidative stress, inflammation, cellular apoptosis and death, and cell cycle regulation. Sirt2 is one of sirtuins family, which is NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase. However, there are a few reports about the role of Sirt2 on cisplatin-induced renal injury. In this study, we evaluated the effect of Sirt2 on renal injury induced by cisplatin.

Methods

We used Sirt2 knockout mice (B6.129-Sirt2tm1.1Fwa/J, Sirt2KO) and their wild type mice (C57BL/6, WT mice). Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin (20 mg/kg). After 3 days after cisplatin injection, blood and kidney tissues were harvested. Renal function and histology were evaluated. Tubular apoptosis and reactive oxygen species were evaluated by immunohistochemistry. Intercellular adhesion molecule (ICAM)-1 and acetyl-p65 were evaluated by Western blot analyses.

Results

After induction of cisplatin nephrotoxicity, renal function measured by serum BUN and creatinine was significantly improved in Sirt2KO mice group at 72 h after cisplatin treatment compared to WT mice. At 72 h after cisplatin treatment, tubular injury score was significantly decreased in Sirt2KO mice compared to WT mice. TUNEL positive tubular cells and renal caspase-3 expression were decreased in Sirt2KO mice compared to WT mice after cisplatin treatment. Cisplatin-induced increases of dihydrorhodamine-123 (DHR, a reactive oxygen species marker)-positive tubular cells were significantly suppressed in Sirt2KO mice compared to WT mice. Finally, cisplatin-induced increases of ICAM-1 and acetyl-p65 expression in Western blot or immunohistochemistry were decreased in Sirt2KO mice.

Conclusion

Sirt2 KO might have important pathophysiologic role in cisplatin-induced renal injury with regulation of apoptosis, a reactive oxygen species and inflammation.

Funding

  • Government Support - Non-U.S.