Journal Article

Programmed necrosis in acute kidney injury

Andreas Linkermann, Federica De Zen, Joel Weinberg, Ulrich Kunzendorf and Stefan Krautwald

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 27, issue 9, pages 3412-3419
Published in print September 2012 | ISSN: 0931-0509
Published online September 2012 | e-ISSN: 1460-2385 | DOI:
Programmed necrosis in acute kidney injury

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Programmed cell death (PCD) had been widely used synonymously to caspase-mediated apoptosis until caspase-independent cell death was described. Identification of necrosis as a regulated process in ischaemic conditions has recently changed our understanding of PCD. At least three pathways of programmed necrosis (PN) have been identified. First, receptor-interacting protein kinase 3 (RIP3)-dependent necroptosis causes organ failure following stroke, myocardial infarction and renal ischaemia/reperfusion injury. Necroptosis can be mediated either by a large intracellular caspase-8-containing signalling complex called the ripoptosome or by the RIP1-/RIP3-containing necroptosome and is controlled by a caspase-8/FLICE inhibitory proteinlong heterodimer at least in the latter case. Second, mitochondrial permeability transition mediates apoptotic or necrotic stimuli and depends on the mitochondrial protein cyclophilin D. The third PN pathway involves the poly(ADP-ribose) polymerase-calpain axis that contributes to acute kidney injury (AKI). Preclinical interference with the PN pathways therefore raises expectations for the future treatment of ischaemic conditions. In this brief review, we aim to summarize the clinically relevant PCD pathways and to transfer the basic science data to settings of AKI. We conclude that pathologists were quite right to refer to ischaemic kidney injury as ‘acute tubular necrosis’.

Keywords: AKI; necroptosis; programmed cell death; RIP1; RIP3

Journal Article.  4640 words.  Illustrated.

Subjects: Nephrology

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