von Maessenhausen, Anne and Tonnus, Wulf and Himmerkus, Nina and Parmentier, Simon and Saleh, Danish and Rodriguez, Diego and Ousingsawat, Jiraporn and Ang, Rosalind L. and Weinberg, Joel M. and Sanz, Ana B. and Ortiz, Alberto and Zierleyn, Adrian and Becker, Jan Ulrich and Baratte, Blandine and Desban, Nathalie and Bach, Stephane and Schiessl, Ina Maria and Nogusa, Shoko and Balachandran, Siddharth and Anders, Hans Joachim and Ting, Adrian T. and Bleich, Markus and Degterev, Alexei and Kunzelmann, Karl and Bornstein, Stefan R. and Green, Douglas R. and Hugo, Christian and Linkermann, Andreas (2018) Phenytoin inhibits necroptosis. CELL DEATH & DISEASE, 9: 359. ISSN 2041-4889,
Full text not available from this repository. (Request a copy)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: | Article |
|---|---|
| Uncontrolled Keywords: | NONAPOPTOTIC CELL-DEATH; MIXED LINEAGE KINASE; REGULATED NECROSIS; RIP1 KINASE; DOMAIN-LIKE; INFLAMMATION; DOWNSTREAM; INJURY; DISCOVERY; POTENT; |
| Subjects: | 500 Science > 570 Life sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Physiologie Biology, Preclinical Medicine > Institut für Physiologie > Prof. Dr. Karl Kunzelmann |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Mar 2020 09:31 |
| Last Modified: | 12 Mar 2020 09:31 |
| URI: | https://pred.uni-regensburg.de/id/eprint/14911 |
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