Pyroptosis: A New Frontier in Kidney Diseases

Abstract

Pyroptosis is a pattern of programmed cell death that significantly differs from apoptosis and autophagy in terms of cell morphology and function. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family-mediated membrane perforation, cell collapse, and the release of inflammatory factors, including IL-1β and IL-18. In recent years, with the rise of pyroptosis research, scholars have devoted time to study the mechanism of pyroptosis in kidney-related diseases. Pyroptosis is probably involved in kidney diseases through two pathways: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. In addition, some scholars have identified targets for the treatment of kidney-related diseases from the viewpoint of pyroptosis and developed corresponding medicines, which may become a recommendation for prognosis, targeted treatment, and clinical diagnosis of kidney diseases. This paper focuses on the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroptosis in the development and progression of kidney diseases. It presents a more in-depth understanding of the pathogenesis of kidney diseases and introduces novel therapeutic targets for the prevention and clinical treatment of kidney diseases.

Figure 1

Canonical caspase-1-dependent and noncanonical caspase-4/5/11-mediated pyroptosis pathways [20, 33, 36, 37, 39, 43, 44, 48, 49]. The canonical pyroptosis signaling pathway: the NLRP3 inflammatory body is activated by pathogen- associated molecular pattern (PAMP) or damage-associated molecular pattern (DAMP), and the AIM2 inflammatory body is activated by dsDNA. They induce the activation of downstream caspase-1. On one hand, this promotes the release of inflammatory factors IL-1β and IL-18; on the other hand, this specifically cleaves GSDMD. The GSDMD-N terminal fragment aggregates at the cell membrane to cause membrane perforation and induce pyroptosis. Noncanonical pyroptosis signaling pathway: lipopolysaccharide (LPS) directly activates caspase-11 (human homology caspase-4/5) then cleaves GSDMD to form the GSDMD-N terminal, inducing pyroptosis. Pannexin-1 is cleaved and lysed by the activated caspase-11 (homologous to human caspase-4/5), which damages the channel for membrane small molecule release, leads to leakage of intracellular ATP, activates the ligand-gated channels (P2X7) of purinergic receptor P2X, accelerates K⁺ efflux, mediates the NLRP3/caspase-1 signaling pathway, and indirectly promotes the release of inflammatory factors IL-1β and IL-18.