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

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-alpha in the kidney and evaluated the modification of Puma-alpha expression and RTC death by in vitro treatment with pifithrin-alpha (PFT-alpha), a specific p53 inhibitor, or Puma-et-specific small interfering RNA (siRNA). Key findings: While no immunoreactivity for anti-p53- and anti-Puma-alpha antibody was detected in the control rat kidney, de novo expression of p53 and Puma-alpha 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-alpha inhibited upregulation of Puma-alpha, and inhibition of Puma-alpha, either by PFT-alpha or by Puma-alpha-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. (C) 2008 Elsevier Inc. All rights reserved.