Pharmacological activation of sirt1 ameliorates cisplatin-induced acute kidney injury by suppressing apoptosis, oxidative stress, and inflammation in mice

Jung Yeon Kim, Jungmin Jo, Kiryeong Kim, Hyun Jin An, Mi Gyeong Gwon, Hyemin Gu, Hyun Ju Kim, A. Young Yang, Sung Woo Kim, Eon Ju Jeon, Jae Hyung Park, Jaechan Leem, Kwan Kyu Park

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Sirtuin 1 (Sirt1) is an essential modulator of cellular metabolism and has pleiotropic effects. It was recently reported that Sirt1 overexpression in kidney tubule ameliorates cisplatin-induced acute kidney injury (AKI). However, whether pharmacological activation of Sirt1 also has a beneficial effect against the disease remains unclear. In this study, we aimed to evaluate whether SRT1720, a potent and specific activator of Sirt1, could ameliorate cisplatin-induced AKI. We found that SRT1720 treatment ameliorated cisplatin-induced acute renal failure and histopathological alterations. Increased levels of tubular injury markers in kidneys were significantly attenuated by SRT1720. SRT1720 treatment also suppressed caspase-3 activation and apoptotic cell death. Increased expression of 4-hydroxynonenal, elevated malondialdehyde level, and decreased ratio of reduced glutathione/oxidized glutathione after cisplatin injection were significantly reversed by SRT1720. In addition, SRT1720 treatment decreased renal expression of pro-inflammatory cytokines and prevented macrophage infiltration into damaged kidneys. We also showed that the therapeutic effects of SRT1720 were associated with reduced acetylation of p53 and nuclear factor kappa-B p65 and preservation of peroxisome function, as evidenced by recovered expression of markers for number and function of peroxisome. These results suggest that Sirt1 activation by SRT1720 would be a useful therapeutic option for cisplatin-induced AKI.

Original languageEnglish
Article number322
JournalAntioxidants
Volume8
Issue number8
DOIs
StatePublished - Aug 2019

Keywords

  • Acute kidney injury
  • Apoptosis
  • Cisplatin
  • Inflammation
  • Oxidative stress
  • SRT1720
  • Sirtuin 1

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