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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity

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Author(s):
Tristao, Vivian Regina [1] ; Pessoa, Edson A. [1] ; Nakamichi, Renata [1] ; Reis, Luciana A. [1] ; Batista, Marcelo Costa [1] ; Durao Junior, Marcelino de Souza [1] ; Martins Monte, Julio Cesar [1]
Total Authors: 7
Affiliation:
[1] Univ Fed Sao Paulo, Sao Paulo - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Apoptosis; v. 21, n. 1, p. 51-59, JAN 2016.
Web of Science Citations: 14
Abstract

Necroptosis is a nonapoptotic cell death pathway. We aim to study the effect of necrostatin-1 (a specific necroptosis inhibitor) in cisplatin-induced injury. We analyzed the effect of the combined use of inhibitors of apoptosis (z-vad) and necroptosis (necrostatin-1) in acute kidney injury by cisplatin in human proximal tubule cells. Our results showed moderate effectiveness in cytoprotection after treatment with z-vad. But the concomitant use of inhibitors (z-vad and necrostatin-1) presented synergistic and additive protection. The present study analyzed the caspase-3 activity and we observed a significant decrease in the group treated with z-vad and cisplatin. However we did not observe changes in the group treated with both inhibitors (z-vad and necrostatin-1) and cisplatin. Thus, demonstrating that necroptosis is a caspase-independent mechanism. We also analyzed the effect of necrostatin-1 in vivo model. C57BL/6 mice were treated with cisplatin and/or inhibitors. The concomitant use of inhibitors (z-vad and necrostatin-1) recovered renal function and decreased levels of urinary Ngal. Additionally, we analyzed the expression of RIP-1, a specific marker for necroptosis. In animals treated with cisplatin and z-VAD levels of RIP-1 were higher. This result reinforces that necroptosis occurs only in conditions where apoptosis was blocked. However, the use of both inhibitors (z-vad and necrostatin-1) provided additional protection. In conclusion, our study has a significant potential to show in vitro and in vivo protection obtained by necrostatin-1. Therefore, our results suggest that necroptosis may be an important mechanism of cell death after kidney injury. (AU)

FAPESP's process: 08/09773-4 - The contribution of necroptosis and apoptosis during acute kidney injury
Grantee:Júlio César Martins Monte
Support type: Regular Research Grants