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

Autor(es)

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]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Apoptosis; v. 21, n. 1, p. 51-59, JAN 2016.
• Citações Web of Science: 14

Resumo

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)

• Processo FAPESP: 08/09773-4 - Estudo da participação dos fenômenos de necroptose e apoptose em modelo de lesão renal aguda
• Beneficiário: Júlio César Martins Monte
• Modalidade de apoio: Auxílio à Pesquisa - Regular