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Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney

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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.

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Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research (H.Y. 19790579) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. We thank Nippon Kayaku Co. Ltd. (Tokyo, Japan) for kindly providing the CDDP for this study.

Conflict of interest

There is no declared conflict of interest in this study.

Author information

Authors and Affiliations

  1. First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi Ward, Hamamatsu, Shizuoka, 431-3192, Japan

    Yukitoshi Sakao, Takayuki Tsuji, Hideo Yasuda, Akashi Togawa, Yoshihide Fujigaki & Akira Hishida

  2. Division of Blood Purification, Hamamatsu University School of Medicine, Shizuoka, Japan

    Akihiko Kato

  3. First Department of Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Tomoaki Kahyo

  4. Department of Molecular Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Mitsutoshi Setou

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  1. Yukitoshi Sakao
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  2. Akihiko Kato
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Correspondence to Yukitoshi Sakao.

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Sakao, Y., Kato, A., Tsuji, T. et al. Cisplatin induces Sirt1 in association with histone deacetylation and increased Werner syndrome protein in the kidney. Clin Exp Nephrol 15, 363–372 (2011). https://doi.org/10.1007/s10157-011-0421-5

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  • DOI: https://doi.org/10.1007/s10157-011-0421-5

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