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

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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.

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Acknowledgments

This study was funded by Grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) No. 08/09773-4, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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Authors and Affiliations

  1. Federal University of São Paulo, Rua Pedro de Toledo, 740, 2º andar, São Paulo, Brazil

    Vivian Regina Tristão, Edson A. Pessoa, Renata Nakamichi, Luciana A. Reis, Marcelo Costa Batista, Marcelino de Souza Durão Junior & Júlio Cesar Martins Monte

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  1. Vivian Regina Tristão
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  2. Edson A. Pessoa
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  3. Renata Nakamichi
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  4. Luciana A. Reis
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  5. Marcelo Costa Batista
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  6. Marcelino de Souza Durão Junior
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  7. Júlio Cesar Martins Monte
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Correspondence to Vivian Regina Tristão.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution.

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Tristão, V.R., Pessoa, E.A., Nakamichi, R. et al. Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity. Apoptosis 21, 51–59 (2016). https://doi.org/10.1007/s10495-015-1190-5

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  • DOI: https://doi.org/10.1007/s10495-015-1190-5

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