1. Synergistic effect of apoptosis and necroptosis inhibitors in cisplatin-induced nephrotoxicity.
- Author
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Tristão VR, Pessoa EA, Nakamichi R, Reis LA, Batista MC, Durão Junior Mde S, and Monte JC
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury pathology, Acute-Phase Proteins genetics, Acute-Phase Proteins urine, Animals, Blood Urea Nitrogen, Caspase 3 genetics, Caspase 3 metabolism, Cell Death drug effects, Cell Line, Cisplatin toxicity, Creatinine blood, Cytoprotection genetics, Drug Synergism, GTPase-Activating Proteins genetics, GTPase-Activating Proteins metabolism, Gene Expression Regulation, Humans, Kidney Function Tests, Kidney Tubules, Proximal metabolism, Kidney Tubules, Proximal pathology, Lipocalin-2, Lipocalins genetics, Lipocalins urine, Male, Mice, Mice, Inbred C57BL, Oncogene Proteins genetics, Oncogene Proteins urine, Signal Transduction, Acute Kidney Injury genetics, Acute Kidney Injury prevention & control, Imidazoles pharmacology, Indoles pharmacology, Kidney Tubules, Proximal drug effects, Oligopeptides pharmacology
- 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.
- Published
- 2016
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