Correction to: Phenytoin inhibits necroptosis
| Autor: | Christian Hugo, Jan U. Becker, Shoko Nogusa, Nathalie Desban, Ana Belen Sanz, Hans-Joachim Anders, Andreas Linkermann, Douglas R. Green, Karl Kunzelmann, Stefan R. Bornstein, Rosalind L. Ang, Simon Parmentier, Danish Saleh, Alexei Degterev, Ina Maria Schiessl, Markus Bleich, Siddharth Balachandran, Adrian T. Ting, Stéphane Bach, Diego Rodriguez, Joel M. Weinberg, Adrian Zierleyn, Nina Himmerkus, Anne von Mässenhausen, Alberto Ortiz, Wulf Tonnus, Jiraporn Ousingsawat, Blandine Baratte |
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| Přispěvatelé: | University of Zurich, Linkermann, Andreas |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Phenytoin
Male Cancer Research Necroptosis Biopsy Immunology 10265 Clinic for Endocrinology and Diabetology 2804 Cellular and Molecular Neuroscience 610 Medicine & health 1307 Cell Biology Cellular and Molecular Neuroscience Gene Knockout Techniques Mice Necrosis medicine Animals Humans 1306 Cancer Research Mice Knockout 2403 Immunology Tumor Necrosis Factor-alpha Philosophy Correction Cell Biology Acute Kidney Injury Systemic Inflammatory Response Syndrome Mice Inbred C57BL Disease Models Animal Receptor-Interacting Protein Serine-Threonine Kinases Reperfusion Injury Anticonvulsants Neuroscience HT29 Cells Protein Kinases medicine.drug |
| Zdroj: | Cell Death & Disease |
| DOI: | 10.5167/uzh-208300 |
| Popis: | Receptor-interacting protein kinases 1 and 3 (RIPK1/3) have best been described for their role in mediating a regulated form of necrosis, referred to as necroptosis. During this process, RIPK3 phosphorylates mixed lineage kinase domain-like (MLKL) to cause plasma membrane rupture. RIPK3-deficient mice have recently been demonstrated to be protected in a series of disease models, but direct evidence for activation of necroptosis in vivo is still limited. Here, we sought to further examine the activation of necroptosis in kidney ischemia-reperfusion injury (IRI) and from TNFα-induced severe inflammatory response syndrome (SIRS), two models of RIPK3-dependent injury. In both models, MLKL-ko mice were significantly protected from injury to a degree that was slightly, but statistically significantly exceeding that of RIPK3-deficient mice. We also demonstrated, for the first time, accumulation of pMLKL in the necrotic tubules of human patients with acute kidney injury. However, our data also uncovered unexpected elevation of blood flow in MLKL-ko animals, which may be relevant to IRI and should be considered in the future. To further understand the mode of regulation of cell death by MLKL, we screened a panel of clinical plasma membrane channel blockers and we found phenytoin to inhibit necroptosis. However, we further found that phenytoin attenuated RIPK1 kinase activity in vitro, likely due to the hydantoin scaffold also present in necrostatin-1, and blocked upstream necrosome formation steps in the cells undergoing necroptosis. We further report that this clinically used anti-convulsant drug displayed protection from kidney IRI and TNFα-induces SIRS in vivo. Overall, our data reveal the relevance of RIPK3-pMLKL regulation for acute kidney injury and identifies an FDA-approved drug that may be useful for immediate clinical evaluation of inhibition of pro-death RIPK1/RIPK3 activities in human diseases. |
| Databáze: | OpenAIRE |
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