title: Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney.
abstract: BACKGROUND
  Sirt1, a mammalian homolog of silent information regulator 2 (Sir2), is the founding member of class III histone deacetylase (HDAC).
  
  
  METHODS
  In this study, we examined whether Sirt1 is involved in the modification of acetylated histone H3, acetylated p53 and Werner syndrome protein (WRN), which is stabilized by Sirt1-mediated deacetylation, in cisplatin (CDDP)-induced acute renal failure (ARF) in rats.
  
  
  RESULTS
  Administration of CDDP (5 mg/kg body weight) caused an increase in the Sirt1 protein level by 6 h; this increase peaked at day 5 and declined until day 14. Sirt1 was induced to a greater extent in rats with severe ARF. In contrast, HDAC3 and HDAC5 were not induced within 24 h after CDDP administration. The level of acetylated histone H3 in the kidney decreased early, i.e., at 6 h, and was minimal at day 5, after which the level gradually increased by day 14. CDDP marginally induced acetylated p53 within 24 h after administration. Increased WRN also became evident at 6 h, and continued to be upregulated until day 5, accompanied by an increase in proliferating cell nuclear antigen (PCNA). Transfection of Sirt1 to human embryonic kidney 293 cells mitigated the CDDP-induced cellular damage.
  
  
  CONCLUSIONS
  These findings collectively suggest that CDDP increases the level of Sirt1 protein in the kidneys in association with histone H3 deacetylation and increased WRN and PCNA production. The induced Sirt1 may work defensively to mitigate CDDP-induced tubular damage by inactivating core histone transcriptionally, and by repairing DNA damage.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan. yuksakao@hama-med.ac.jp.
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Sakao
authors.affiliation: Division of Blood Purification, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kato
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan.
authors.forename: Akashi
authors.initials: A
authors.lastname: Togawa
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Fujigaki
authors.affiliation: First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Kahyo
authors.affiliation: Department of Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Setou
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hishida
mesh_terms: D058186:Acute Kidney Injury / Q000503:physiopathology; D000818:Animals; D002945:Cisplatin / Q000494:pharmacology*; D004265:DNA Helicases / Q000096:biosynthesis*; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000071657:Werner Syndrome Helicase; D000099186:Histone Deacetylase 3
chemical_list: D002945:Cisplatin; D004265:DNA Helicases; D006655:Histone Deacetylases; D018809:Proliferating Cell Nuclear Antigen; D056564:Sirtuin 1; D016159:Tumor Suppressor Protein p53; D000071657:Werner Syndrome Helicase; D000099186:Histone Deacetylase 3; C488368:Sirt1 protein, rat; C561572:WRN protein, rat