Involvement of p53-transactivated Puma in cisplatin-induced renal tubular cell death

Kazuhiko Tsuruya, Hideki Yotsueda, Hirofumi Ikeda, Masatomo Taniguchi, Kohsuke Masutani, Hideko Hayashida, Hideki Hirakata, Mitsuo Iida

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28 Citations (Scopus)

Abstract

Aims: The tumor suppressor protein p53 plays a critical role as a determinant of cell survival when cells are exposed to various toxic stresses, by preventing growth arrest, replication of damaged DNA, and apoptosis. A novel p53-dependent proapoptotic gene, Puma (p53 upregulated modulator of apoptosis) is thought to participate in this process. Recently, p53 was reported to play an essential role in cisplatin-induced renal tubular cell (RTC) death. The objective of the present study was to elucidate the roles of p53 and Puma in cisplatin-induced RTC death. Main methods: We examined the in vivo expression of p53 and Puma-α in the kidney and evaluated the modification of Puma-α expression and RTC death by in vitro treatment with pifithrin-α (PFT-α), a specific p53 inhibitor, or Puma-α-specific small interfering RNA (siRNA). Key findings: While no immunoreactivity for anti-p53- and anti-Puma-α antibody was detected in the control rat kidney, de novo expression of p53 and Puma-α was identified in the proximal tubular cells of the outer medulla at 6 h after cisplatin injection. Upregulation of these proteins preceded severe RTC injury. In vitro experiments revealed that PFT-α inhibited upregulation of Puma-α, and inhibition of Puma-α, either by PFT-α or by Puma-α-specific siRNA, decreased RTC death induced by 24-h cisplatin exposure. Significance: Our results indicated that p53 activation mediated cisplatin-induced RTC death through upregulation of Puma, and suggested that inhibition of p53 and Puma is beneficial for the prevention and treatment of cisplatin-induced acute renal failure.

Original languageEnglish
Pages (from-to)550-556
Number of pages7
JournalLife Sciences
Volume83
Issue number15-16
DOIs
Publication statusPublished - Oct 10 2008

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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    Tsuruya, K., Yotsueda, H., Ikeda, H., Taniguchi, M., Masutani, K., Hayashida, H., Hirakata, H., & Iida, M. (2008). Involvement of p53-transactivated Puma in cisplatin-induced renal tubular cell death. Life Sciences, 83(15-16), 550-556. https://doi.org/10.1016/j.lfs.2008.08.002