Programmed necrosis in acute kidney injury.

Area of Science:

• Cellular Biology
• Pathology
• Biochemistry

Background:

• Programmed cell death (PCD) encompasses both caspase-mediated apoptosis and regulated caspase-independent cell death pathways.
• Recent findings identify necrosis as a regulated process in ischemic conditions, expanding the understanding of PCD.
• Three key pathways of programmed necrosis (PN) have been identified: RIP3-dependent necroptosis, mitochondrial permeability transition, and the poly(ADP-ribose) polymerase-calpain axis.

Discussion:

• Receptor-interacting protein kinase 3 (RIP3)-dependent necroptosis, mediated by the ripoptosome or necroptosome, leads to organ failure in stroke, myocardial infarction, and renal ischemia/reperfusion injury.
• Mitochondrial permeability transition, regulated by cyclophilin D, can mediate both apoptotic and necrotic stimuli.
• The poly(ADP-ribose) polymerase-calpain axis is implicated in acute kidney injury (AKI).

Key Insights:

• Necroptosis involves complex signaling platforms like the ripoptosome and necroptosome, with regulation by caspase-8/FLICE inhibitory protein(long) heterodimers.
• Cyclophilin D plays a critical role in regulating mitochondrial transitions, influencing cell death outcomes.
• The identified PN pathways provide mechanistic insights into ischemic organ damage, particularly in AKI.

Outlook:

• Preclinical interventions targeting PN pathways show promise for treating ischemic conditions.
• Translating basic science findings on PCD pathways to clinical settings, especially AKI, is a key future direction.
• The review supports the historical classification of ischemic kidney injury as 'acute tubular necrosis' based on underlying PN mechanisms.