Nec-1 Protects against Nonapoptotic Cell Death in Cisplatin-Induced Kidney Injury

Abstract

Background/aims: Necrostatin-1 (Nec-1) inhibits necroptosis, a nonapoptotic cell death pathway. Acute kidney injury (AKI) is a clinical problem of high incidence and mortality. It involves several mechanisms of cell death. We aim to evaluate the effect of Nec-1 in the toxic kidney injury model by cisplatin. Methods: We analyzed the effect of Nec-1 in AKI by cisplatin in human proximal tubule cells by flow cytometry. Results: Our results show that Nec-1 has no effect on apoptosis in renal tubular epithelial cells (Nec-1 + Cis group 13.4 ± 1.7% vs. Cis group 14.6 ± 1.4%) (p > 0.05). But, in conditions in which apoptosis was blocked by benzyloxy-carbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk) the use of Nec-1 completely reversed cell viability (Nec-1 + Cis + z-VAD group 72.9 ± 6.3% vs. Cis group 35.5 ± 2.2%) (p < 0.05) suggesting that Nec-1 has effect on nonapoptotic cell death (necroptosis). Conclusion: Our findings suggest that the combined use of apoptosis and necroptosis inhibitors can provide additional cytoprotection in AKI. Furthermore, this is the first study to demonstrate that Nec-1 inhibits tubular kidney cell death and restores cell viability via a nonapoptotic mechanism.

• necrostatin-1
• cytoprotection
• necroptosis
• cisplatin
• acute kidney injury

ACKNOWLEDGMENTS

Funding. This work was supported by grants from Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) N° 08/09773-4, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

This study was conducted at the Nephrology Division, Federal University of São Paulo – UNIFESP