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

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

Author Tristao, Vivian Regina Autor UNIFESP Google Scholar
Pessoa, Edson A. Autor UNIFESP Google Scholar
Nakamichi, Renata Autor UNIFESP Google Scholar
Reis, Luciana A. Autor UNIFESP Google Scholar
Batista, Marcelo Costa Autor UNIFESP Google Scholar
Durao Junior, Marcelino de Souza Autor UNIFESP Google Scholar
Martins Monte, Julio Cesar Autor UNIFESP Google Scholar
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.
Keywords Necroptosis
Acute kidney injury
CytoprotectionAcute Kidney Injury
Gelatinase-Associated Lipocalin
Nonapoptotic Cell-Death
Ischemia/Reperfusion Injury
Caspase Activation
Urinary Biomarker
Renal Injury
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Grant number FAPESP: 08/09773-4
Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES).
Date 2016
Published in Apoptosis. Dordrecht, v. 21, n. 1, p. 51-59, 2016.
ISSN 1360-8185 (Sherpa/Romeo, impact factor)
Publisher Springer
Extent 51-59
Access rights Closed access
Type Article
Web of Science ID WOS:000367694200005

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