von Maessenhausen, Anne, Tonnus, Wulf, Himmerkus, Nina ORCID: 0000-0002-2910-6728, Parmentier, Simon, Saleh, Danish, Rodriguez, Diego ORCID: 0000-0003-4771-0221, Ousingsawat, Jiraporn, Ang, Rosalind L., Weinberg, Joel M., Sanz, Ana B., Ortiz, Alberto, Zierleyn, Adrian, Becker, Jan Ulrich ORCID: 0000-0003-2929-8085, Baratte, Blandine, Desban, Nathalie, Bach, Stephane, Schiessl, Ina Maria ORCID: 0000-0003-1613-2000, Nogusa, Shoko, Balachandran, Siddharth, Anders, Hans Joachim, Ting, Adrian T., Bleich, Markus ORCID: 0000-0002-1745-2295, Degterev, Alexei, Kunzelmann, Karl, Bornstein, Stefan R., Green, Douglas R., Hugo, Christian and Linkermann, Andreas ORCID: 0000-0001-6287-9725 (2018). Phenytoin inhibits necroptosis. Cell Death Dis., 9. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-4889

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Abstract

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 TNF alpha-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 anticonvulsant drug displayed protection from kidney IRI and TNF alpha-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
von Maessenhausen, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tonnus, WulfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Himmerkus, NinaUNSPECIFIEDorcid.org/0000-0002-2910-6728UNSPECIFIED
Parmentier, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saleh, DanishUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez, DiegoUNSPECIFIEDorcid.org/0000-0003-4771-0221UNSPECIFIED
Ousingsawat, JirapornUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ang, Rosalind L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weinberg, Joel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sanz, Ana B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortiz, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zierleyn, AdrianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, Jan UlrichUNSPECIFIEDorcid.org/0000-0003-2929-8085UNSPECIFIED
Baratte, BlandineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Desban, NathalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bach, StephaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schiessl, Ina MariaUNSPECIFIEDorcid.org/0000-0003-1613-2000UNSPECIFIED
Nogusa, ShokoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Balachandran, SiddharthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anders, Hans JoachimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ting, Adrian T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bleich, MarkusUNSPECIFIEDorcid.org/0000-0002-1745-2295UNSPECIFIED
Degterev, AlexeiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kunzelmann, KarlUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bornstein, Stefan R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Green, Douglas R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hugo, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Linkermann, AndreasUNSPECIFIEDorcid.org/0000-0001-6287-9725UNSPECIFIED
URN: urn:nbn:de:hbz:38-193032
DOI: 10.1038/s41419-018-0394-3
Journal or Publication Title: Cell Death Dis.
Volume: 9
Date: 2018
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-4889
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NONAPOPTOTIC CELL-DEATH; MIXED LINEAGE KINASE; REGULATED NECROSIS; RIP1 KINASE; DOMAIN-LIKE; INFLAMMATION; DOWNSTREAM; INJURY; DISCOVERY; POTENTMultiple languages
Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19303

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