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Review
. 2021 Oct 11:2021:1173324.
doi: 10.1155/2021/1173324. eCollection 2021.

Mechanisms of Kidney Cell Pyroptosis in Chronic Kidney Disease and the Effects of Traditional Chinese Medicine

Baozhu Ding  1   2 , Guoping Ma  3 , Zinuo Wang  4 , Wenjie Liang  1   2 , Weifang Gao  2
Affiliations
Review

Mechanisms of Kidney Cell Pyroptosis in Chronic Kidney Disease and the Effects of Traditional Chinese Medicine

Baozhu Ding et al. Evid Based Complement Alternat Med. .

Abstract

Chronic kidney disease (CKD) is a major public health issue that is highly prevalent worldwide. Pyroptosis is an important pathological mechanism underlying kidney cell damage in CKD and is associated with the classic caspase-1-mediated pathway and nonclassic caspase-4/5/11-mediated pathway. The NLRP3-caspase-1-GSDMD signaling pathway is the key mechanism of kidney cell pyroptosis in CKD, and noncoding RNAs such as lncRNAs and miRNAs are important regulators of kidney cell pyroptosis in CKD. In addition, the NLRP1/AIM2-caspase-1-GSDMD and caspase-3-GSDME signaling pathways have also been shown to mediate kidney cell pyroptosis. Traditional Chinese medicine (TCM) and extracts can interfere with the occurrence and development of kidney cell pyroptosis in CKD by inhibiting the NLRP3 signaling pathway and oxidative stress, activating Nrf-2 signaling, protecting mitochondrial integrity, regulating AMPK signaling, and regulating TXNIP/NLRP3 axis, which have become increasingly prominent. It is critical to explore the effects of TCM on kidney cell pyroptosis in CKD and its mechanisms to identify targets and develop new and effective drugs.

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Conflict of interest statement

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
Mechanisms of kidney cell pyroptosis in chronic kidney disease. (1) (NLRP3-caspase-1-GSDMD pathway) PAMPs and DAMPs activate NLRP3 molecules, NLRP3 oligomerizing to form the NLRP3 complex, which recruits procaspase-1 monomers through the adapter protein ASC, activating caspase-1. Caspase-1 processes the pro-IL-1β/pro-IL-18 to generate mature IL-1β/IL-18, and in the meantime, GSDMD is cleaved to produce GSDMD-NT, which damage the cell membrane eventually leading to pyroptosis. Then, IL-1β and IL-18 are released extracellularly, initiating the inflammatory response. Simultaneously, pyroptosis promotes the release of intracellular DAMP, further inducing pyroptosis in other cells and forming a positive feedback loop, aggravating renal inflammation damage. (2) (NLRP1-caspase-1-GSDMD pathway) Bacterial muramyl dipeptide, anthrax toxin, etc., can activate the NLRP1 inflammasome. The NLRP1 molecule C-terminal CARD domain can be directly activated by interacting with the CARD domain of procaspase-1, then activating caspase-1. The next steps are similar to the NLRP3 pathway. (3) (AIM2-caspase-1-GSDMD pathway) dsDNA can bind to and activate the C-terminal HIN200 domain of AIM2, and the PYD domain of the activated AIM2 molecule interacts with that of the ASC molecule to activate ASC. The CARD domain of activated ASC combines with the CARD domain of procaspase-1 to form AIM2 inflammasome, and procaspase-1 cuts and activates itself, eventually causing pyroptosis. (4) (LPS-caspase-4/5/11-GSDMD pathway) When the pathogen invades the kidney cells, the component of LPS, lipid A, binds to and activate the CARD domain of caspase-11, thereby cleaving GSDMD and causing pyroptosis. Meanwhile, the gap junction protein 1 (pannexin 1) transmembrane channel is cleaved, forming a pathway, along which the intracellular ATP is released. ATP binds to the membrane P2X7 receptor, opening the nonselective P2X7 positive ion channel, which causes intracellular K+ outflow and extracellular Na+ and Ca2+ inflow, and finally the cell membrane is damaged, leading to pyroptosis. (5) (ATP-caspase-3-GSDME pathway) ATP can activate caspase-3 in macrophages and lyse GSDME protein to produce GSDME-NT. GSDME-NT is similar to GSDMD-NT, leading to membrane pore formation, eventually resulting in pyroptosis.
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