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 language | English (US) |
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Pages (from-to) | 550-556 |
Number of pages | 7 |
Journal | Life Sciences |
Volume | 83 |
Issue number | 15-16 |
DOIs | |
State | Published - Oct 10 2008 |
Keywords
- Acute renal failure
- Cisplatin
- Pifithrin-α
- Puma
- p53
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
- Pharmacology, Toxicology and Pharmaceutics(all)