Abstract
Abstract Regulated necrosis (RN) may result from cyclophilin D (CypD)-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase 1 (RIPK1)- mediated necroptosis, ferroptosis, pyroptosis, NADPH-oxidase (NOX) mediated necrosis and other pathways, but it is currently unclear to what extent these signaling pathways are independent from each other. Especially MPT and necroptosis have been described to contribute to necrotic cell death in kidney ischemia reperfusion injury (IRI). We demonstrate that necroptosis in IRI occurs in mice as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI and the level of protection was significantly stronger than of CypD-deficient mice. Several lines of evidence in vitro and in vivo, including the analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. In addition, we found necroptosis to be completely independent of mitochondria in vitro and therefore generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 (Nec-1) and the MPT inhibitor sanglifehrin A (SfA) confirmed the results with mutant mice. The data demonstrate the pathophysiological co-existence and co-relevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury. Citation Format: Andreas Linkermann. Beyond necroptosis - regulated necrosis in the kidney. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY29-04. doi:10.1158/1538-7445.AM2014-SY29-04
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