Pyroptosis Mechanisms in Acute Kidney Injury

Pyroptosis is a lytic, pro-inflammatory form of programmed cell death driven by the activation of inflammatory caspases and pore-forming gasdermin proteins. In acute kidney injury (AKI), diverse insults such as ischaemia–reperfusion, nephrotoxic drugs and sepsis provoke assembly of inflammasomes—supramolecular platforms that detect danger signals and recruit caspase-1 or its murine equivalent caspase-11. Once activated, caspase-1 cleaves gasdermin D (GSDMD), liberating its N-terminal fragment to form membrane pores, thereby enabling release of interleukin-1β and interleukin-18 and culminating in cell swelling and rupture. A non-classical pathway mediated by caspase-4/5/11 similarly engages GSDMD to amplify tubular epithelial cell injury and interstitial inflammation. Emerging evidence also implicates gasdermin E and caspase-3 in a secondary pyroptotic cascade, particularly under cytotoxic stress. Collectively, these pathways drive tubular cell death, capillary congestion and fibrotic remodelling, exacerbating renal dysfunction. Given its central role in AKI pathogenesis, pyroptosis represents a promising target for therapeutic intervention aimed at preserving renal structure and function.

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Pyroptosis Mechanisms in Acute Kidney Injury publication trend

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Technical terms

Pyroptosis: A form of programmed cell death marked by membrane pore formation, cell swelling and pro-inflammatory cytokine release.

Inflammasome: A multiprotein complex that senses cellular stress or pathogens and activates inflammatory caspases.

Gasdermin D: A pore-forming protein cleaved by inflammatory caspases to execute pyroptosis.

Caspase-1: An inflammatory protease that processes interleukins and cleaves gasdermin D to initiate pyroptosis.

NLRP3 inflammasome: A widely studied sensor complex that detects diverse danger signals and activates caspase-1.

Interleukin-1β: A key pro-inflammatory cytokine released through gasdermin D pores during pyroptosis.

References

1. Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance. Cell Death & Disease (2023).
2. Acetyl-CoA synthetase 2 induces pyroptosis and inflammation of renal epithelial tubular cells in sepsis-induced acute kidney injury by upregulating the KLF5/NF-κB pathway. Cell Communication and Signaling (2024).
3. Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation. Cell Death & Disease (2021).