Pyroptosis: A New Frontier in Kidney Diseases

Zhang, Kejia; Wu, Qi; Jiang, Shanwen; Ding, Lei; Liu, Chaoxia; Xu, Ming; Wang, Ying; Zhou, Yao; Li, Li

doi:10.1155/2021/6686617

Cited by 24 publications

(24 citation statements)

References 108 publications

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“… 35–37 The occurrence and progression of kidney diseases are more or less related to pyroptosis, and the inflammatory body NLRP3 is the most well-studied. 38 , 39 Pyroptosis-related cell death is similar to apoptosis in that both are characterized by DNA fragmentation. However, pyroptosis is regulated by inflammation-associated proteins rather than classical apoptotic-related proteins.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of TRIM8 Protects HK-2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Inhibiting Oxidative Stress-Mediated Apoptosis and Pyroptosis via PI3K/Akt Signal Pathway

Zhang¹,

Líu²,

Yuan³

et al. 2021

DDDT

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Background Acute kidney injury (AKI) emerges as an acute and critical disease. Tripartite motif 8 (TRIM8), one number of the TRIM protein family, is proved to participate in ischemia/reperfusion (I/R) injury. However, whether TRIM8 is involved in renal I/R injury and the associated mechanisms are currently unclear. Purpose This study aimed to investigate the precise role of TRIM8 and relevant mechanisms in renal I/R injury. Materials and Methods In this study, human renal proximal tubular epithelial cells (HK-2 cells) underwent 12 hours of hypoxia and 2 h, 3 h or 4 h of reoxygenation to establish an in vitro hypoxia/reoxygenation (H/R) model. The siRNAs specific to TRIM8 (si-TRIM8) were transfected into HK-2 cells to knockdown TRIM8. The cell H/R model included various groups including Control, H/R, H/R+DMSO, H/R+NAC, si-NC+H/R, si-TRIM8+H/R and si-TRIM8+LY294002+H/R. The cell viability and levels of reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ), mRNA, apoptotic proteins, pyroptosis-related proteins and PI3K/AKT pathway-associated proteins were assessed. Results In vitro, realtime-quantitative PCR and western-blot analysis showed that the mRNA and protein expression of TRIM8 were obviously upregulated after H/R treatment in HK-2 cells. Compared with the H/R model group, knockdown of TRIM8 significantly increased cell viability and reduced the levels of ROS, H 2 O 2 , apoptotic proteins (Cleaved caspasebase-3 and BAX) and pyroptosis-related proteins (NLRP3, ASC, Caspase-1, Caspase-11, IL-1β and GSDMD-N). Western-blot analysis also authenticated that PI3K/AKT pathway was activated after TRIM8 inhibition. The application of 5 mM N-acetyl-cysteine, one highly efficient ROS inhibitor, significantly suppressed the expression of apoptotic proteins and pyroptosis-related proteins. Moreover, the combined treatment of TRIM8 knockdown and LY294002 reversed the effects of inhibiting oxidative stress. Conclusion Knockdown of TRIM8 can alleviate H/R-induced oxidative stress by triggering the PI3K/AKT pathway, thus attenuating pyropyosis and apoptosis in vitro.

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Section: Discussionmentioning

confidence: 99%

Knockdown of TRIM8 Protects HK-2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Inhibiting Oxidative Stress-Mediated Apoptosis and Pyroptosis via PI3K/Akt Signal Pathway

Zhang¹,

Líu²,

Yuan³

et al. 2021

DDDT

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“…Our present results also showed that HDAC11 expression was significantly increased in the aorta of HFD-fed ApoE −/− mice. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family mediated membrane perforation, cell collapse, and the release of pro-inflammatory cytokines such as IL-1β and IL-18 [ 22 ]. It has been reported that GSDMD and GSDME were found to be expressed in the artery [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

et al. 2022

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Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE−/− mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.

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“…Pyroptosis is an inflammatory form of programmed cell death regulating immunity response ( Xiong et al, 2020 ). There are two pathways related to pyroptosis that have been identified: the canonical pathway mediated by caspase-1 and induced by inflammatory bodies such as NLRP3 (NLR family pyrin domain containing 3) and the noncanonical pathway mediated by caspase-4/5/11 and activated by lipopolysaccharide (LPS) ( Yu et al, 2021 ; Zhang et al, 2021 ). The common consequence of the above two pathways is the cleavage of gasdermin-D (GSDMD) into N-terminal fragments of GSDMD (GSDMD-NT), which played an essential role in the pore formation through insertion into the cell membrane and subsequent cellular contents release such as IL-1β and IL-18 ( Evavold et al, 2021 ; Yu et al, 2021 ).…”

Section: Podocyte Loss Due To Cell Deathmentioning

confidence: 99%

Controversies in Podocyte Loss: Death or Detachment?

Yin

et al. 2021

Front. Cell Dev. Biol.

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Glomerular podocytes are characterized by terminally differentiated epithelial cells with limited proliferating ability; thus, podocyte loss could not be fully compensated by podocyte regeneration. A large body of clinical studies collectively demonstrated that podocyte loss correlated with glomerular diseases progression. Both podocyte death and podocyte detachment lead to podocyte loss; however, which one is the main cause remains controversial. Up to date, multiple mechanisms are involved in podocyte death, including programmed apoptotic cell death (apoptosis and anoikis), programmed nonapoptotic cell death (autophagy, entosis, and podoptosis), immune-related cell death (pyroptosis), and other types of cell death (necroptosis and mitotic catastrophe-related cell death). Apoptosis is considered a common mechanism of podocyte loss; however, most of the data were generated in vitro and the evidence of in vivo podocyte apoptosis is limited. The isolation of podocytes in the urine and subsequent culture of urinary podocytes in vitro suggest that detachment of viable podocytes could be another important mechanism for podocyte loss. In this review, we summarize recent advances that address this controversial topic on the specific circumstances of podocyte loss.

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Pyroptosis: A New Frontier in Kidney Diseases

Cited by 24 publications

References 108 publications

Knockdown of TRIM8 Protects HK-2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Inhibiting Oxidative Stress-Mediated Apoptosis and Pyroptosis via PI3K/Akt Signal Pathway

Knockdown of TRIM8 Protects HK-2 Cells Against Hypoxia/Reoxygenation-Induced Injury by Inhibiting Oxidative Stress-Mediated Apoptosis and Pyroptosis via PI3K/Akt Signal Pathway

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells

Controversies in Podocyte Loss: Death or Detachment?

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