Yukitoshi Sakao1, Akihiko Kato2, Takayuki Tsuji3, Hideo Yasuda3, Akashi Togawa3, Yoshihide Fujigaki3, Tomoaki Kahyo4, Mitsutoshi Setou5, Akira Hishida3. 1. 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. 2. Division of Blood Purification, Hamamatsu University School of Medicine, Shizuoka, Japan. 3. First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan. 4. First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan. 5. Department of Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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.
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 humanembryonic 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: Ana M Rodríguez-López; Dean A Jackson; Jan O Nehlin; Francisco Iborra; Anna V Warren; Lynne S Cox Journal: Mech Ageing Dev Date: 2003-02 Impact factor: 5.432
Authors: Sanjay Koul; James M McKiernan; Gopeshwar Narayan; Jane Houldsworth; Jennifer Bacik; Deborah L Dobrzynski; Adel M Assaad; Mahesh Mansukhani; Victor E Reuter; George J Bosl; Raju S K Chaganti; Vundavalli V V S Murty Journal: Mol Cancer Date: 2004-05-18 Impact factor: 27.401