Relevance of the Pyroptosis-Related Inflammasome Pathway in the Pathogenesis of Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD) in many developed and developing countries. Pyroptosis is a recently discovered form of programmed cell death (PCD). With progress in research on DKD, researchers have become increasingly interested in elucidating the role of pyroptosis in DKD pathogenesis. This review focuses on the three pathways of pyroptosis generation: the canonical inflammasome, non-canonical inflammasome, and caspase-3-mediated inflammasome pathways. The molecular and pathophysiological mechanisms of the pyroptosis-related inflammasome pathway in the development of DKD are summarized. Activation of the diabetes-mediated pyroptosis-related inflammasomes, such as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Toll-like receptor 4 (TLR4), caspase-1, interleukin (IL)-1β, and the IL-18 axis, plays an essential role in DKD lesions. By inhibiting activation of the TLR4 and NLRP3 inflammasomes, the production of caspase-1, IL-1β, and IL-18 is inhibited, thereby improving the pathological changes associated with DKD. Studies using high-glucose-induced cell models, high-fat diet/streptozotocin-induced DKD animal models, and human biopsies will help determine the spatial and temporal expression of DKD inflammatory components. Recent studies have confirmed the relationship between the pyroptosis-related inflammasome pathway and kidney disease. However, these studies are relatively superficial at present, and the mechanism needs further elucidation. Linking these findings with disease activity and prognosis would provide new ideas for DKD research.

Keywords: diabetic kidney disease; inflammasome pathway; pathogenesis; pyroptosis-related; targeted inhibition.

Figure 1

The three kinds of inflammasome pathways associated with pyroptosis. (1) Canonical inflammasome pathway associated with pyroptosis; (2) non-canonical inflammasome pathway associated with pyroptosis; (3) caspase-3 mediated inflammasome pathway associated with pyroptosis. LPS, Lipopolysaccharide.

Figure 2

Promotion of inflammasome pathways associated with pyroptosis of cells in the kidney (glomerular endothelial cells, tubular epithelial cells, podocytes, tubular epithelial cells) under high-sugar or diabetes conditions, leading to diabetic kidney disease (DKD). In renal cells stimulated by high glucose (HG): (1) ROS/TXNIP/NLRP3 inflammasome signaling pathway, (2) TLR4/NF-κB inflammasome signaling pathway, (3) AMPK/SIRT1/NF-κB inflammasome signaling pathway, or (4) lncRNA)-related signaling pathways, they all activate pro-caspase-1 to become mature caspase-1. Caspase-1 cleaves GSDMD and activates the inactive pro IL-1β and pro-IL-18 to become mature IL-1β and IL-18, and the released GSDMD-NT forms a pore in the cell membrane, ultimately leading to DKD. ROS, Reactive oxygen species; TXNIP, Thioredoxin-interacting protein; AMPK, Adenosine 5’-monophosphate (AMP)-activated protein kinase; SIRT1, Silent information regulation 2 homolog1; NF-κB, Nuclear factor kappa-B.