title: Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury.
abstract: Loss of kidney function in renal ischemia/reperfusion injury is due to programmed cell death, but the contribution of necroptosis, a newly discovered form of programmed necrosis, has not been evaluated. Here, we identified the presence of death receptor-mediated but caspase-independent cell death in murine tubular cells and characterized it as necroptosis by the addition of necrostatin-1, a highly specific receptor-interacting protein kinase 1 inhibitor. The detection of receptor-interacting protein kinase 1 and 3 in whole-kidney lysates and freshly isolated murine proximal tubules led us to investigate the contribution of necroptosis in a mouse model of renal ischemia/reperfusion injury. Treatment with necrostatin-1 reduced organ damage and renal failure, even when administered after reperfusion, resulting in a significant survival benefit in a model of lethal renal ischemia/reperfusion injury. Unexpectedly, specific blockade of apoptosis by zVAD, a pan-caspase inhibitor, did not prevent the organ damage or the increase in urea and creatinine in vivo in renal ischemia/reperfusion injury. Thus, necroptosis is present and has functional relevance in the pathophysiological course of ischemic kidney injury and shows the predominance of necroptosis over apoptosis in this setting. Necrostatin-1 may have therapeutic potential to prevent and treat renal ischemia/reperfusion injury.
authors.affiliation: Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.forename: Jan H
authors.initials: JH
authors.lastname: Bräsen
authors.forename: Nina
authors.initials: N
authors.lastname: Himmerkus
authors.forename: Shuya
authors.initials: S
authors.lastname: Liu
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Huber
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kunzendorf
authors.forename: Stefan
authors.initials: S
authors.lastname: Krautwald
mesh_terms: D000818:Animals; D017209:Apoptosis; D061945:Caspase Inhibitors; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D007668:Kidney / Q000201:enzymology / Q000293:injuries* / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D015427:Reperfusion Injury / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*
chemical_list: D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007093:Imidazoles; D007211:Indoles; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C507699:necrostatin-1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse