The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury

Miao, Naijun; Yin, Fang‐Fang; Xie, Hongyan; Wang, Yanzhe; Xu, Yiang; Shen, Yang; Xu, Dan; Yin, Jianyong; Wang, Bao; Zhou, Zhuanli; Qian, Cheng; Chen, Panpan; Xue, Hong; Zhou, Li; Li, Jun; Wang, Xiaoxia; Zhang, Wei; Lü, Limin

doi:10.1016/j.kint.2019.04.035

Cited by 169 publications

(135 citation statements)

References 48 publications

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…[4][5][6] Although initially thought to be specific for immune cells, it has been recently shown that pyroptosis can be functional in nonimmune cells and multiple diseases. 4,7,8) Our previous study indicated that pyroptosis is involved in tubular injury in diabetes, as evidenced by GSDMD p30 fragment generation and flow cytometry analysis. 9) Understanding the molecular cascades regulating pyroptosis will yield additional targets for DKD treatment.…”

Section: Introductionmentioning

confidence: 94%

circACTR2: A Novel Mechanism Regulating High Glucose-Induced Fibrosis in Renal Tubular Cells via Pyroptosis

et al. 2020

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current therapies for DKD are insufficient. Therefore, there is an urgent need for identifying new therapies. An increasing number of micro RNAs (miRNAs) and long noncoding RNAs (lncRNAs) have been demonstrated to modulate the progression of diabetic kidney disease. Nevertheless, until now, there have been few reports evaluating the relevance of circular RNAs (circRNAs) in DKD. circRNAs have been reported to regulate the occurrence and development of multiple diseases. In this study, we intended to explore the circRNA expression profiles and determine the role of circRNA in DKD. We identified a series of dysregulated circRNAs in glucose-stressed HK-2 cells using circRNA microarray analysis. Among the candidate circRNAs, we found that circACTR2 was upregulated and may be involved in inflammation and pyroptosis. Knockdown of circACTR2 significantly decreased pyroptosis, interleukin (IL)-1β release and collagen IV and fibronectin production, indicating the effective regulation by circACTR2 of cell death and inflammation. Overall, our study identified a new circRNA, circACTR2, that regulates high glucose-induced pyroptosis, inflammation and fibrosis in proximal tubular cells. The present study preliminarily explores the role of circRNAs in pyroptosis of tubular cells, and provides novel insight into the pathogenesis of DKD and new therapeutic strategies.

show abstract

Section: Introductionmentioning

confidence: 94%

circACTR2: A Novel Mechanism Regulating High Glucose-Induced Fibrosis in Renal Tubular Cells via Pyroptosis

et al. 2020

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…7 Researchers have found that pyroptosis had an indispensable role in renal ischemia-reperfusion injury and contrast-induced acute kidney injury. 8,9 Whether pyroptoticlike secondary necrosis takes a role in kidney diseases remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis

Su¹,

Wang²,

Zhang³

et al. 2020

DMSO

View full text Add to dashboard Cite

These authors contributed equally to this workBackground: Apoptosis has been repeatedly linked with diabetic kidney disease (DKD), which is a programmed cell death mediated by effector caspases-3, 6 and 7, targeting >600 substrates. However, the pathophysiologic correlations of this process remain obscure. As a putative tumor suppressor, gasdermin E (GSDME) was recently reported to be cleaved by caspase-3 to produce a GSDME-N fragment which targets the plasma membrane to switch apoptosis to secondary necrosis. However, it remains elusive whether GSDME is involved in the regulation of DKD. Methods: To evaluate the therapeutic potential of caspase-3 inhibition in DKD, we administered caspase-3 inhibitor Z-DEVD-FMK to STZ-induced diabetic mice for eight weeks. Albuminuria, renal function, pathological changes, and indicators of secondary necrosis and fibrosis were evaluated. In vitro, human tubule epithelial cells (HK-2 cells) were subjected to high-glucose treatment. Secondary necrosis was determined by LDH release, GSDME cleavage, and morphological feature under confocal microscopy. Z-DEVD-FMK and GSDME inhibition by shRNA were administered to suppress the cleavage and expression of GSDME. Flow cytometry, cytotoxicity assay and immunoblot were used to assess cell death and fibrogenesis. Results: Caspase-3 inhibition by Z-DEVD-FMK ameliorated albuminuria, renal function, and tubulointerstitial fibrosis in diabetic mice. The nephroprotection mediated by Z-DEVD-FMK was potentially associated with inhibition of GSDME. In vitro, molecular and morphological features of secondary necrosis were observed in glucose-stressed HK-2 cells, evidenced by active GSDME cleavage, ballooning of the cell membrane, and release of cellular contents. Here we showed that caspase-3 inhibition prevented GSDME activation and cell death in glucose-treated tubular cells. Specifically, knocking down GSDME directly inhibited secondary necrosis and fibrogenesis. Conclusion: These data suggest GSDME-dependent secondary necrosis plays a crucial role in renal injury, and provides a new insight into the pathogenesis of DKD and a promising target for its treatment.

show abstract

“…Unfortunately, although Gsdmd protein was found to be significantly increased at day 7 by the immunoblot assay (Figure 1, K-L), our untargeted MS approach was unable to detect it. Gsdmd-dependent pyroptosis cell death has been revealed for the first time in non-septic AKI in a very recent study 43 . Our data indicated that Gsdmd expression remained at a low level at the acute stage and drastically increased at the chronic phase.…”

Section: Discussionmentioning

confidence: 94%

“…This pathway has only recently been associated with kidney injury 43 . Gasdmd was significantly increased in the injured kidneys at day 7 after CLP (Figure 1K, 1L).…”

Section: Resultsmentioning

confidence: 99%

The global proteome and phosphoproteome landscape of sepsis-induced kidney injury

Lin

Platt

Zhou

et al. 2020

Preprint

View full text Add to dashboard Cite

Sepsis-induced acute kidney injury (S-AKI) is the most common complication in hospitalized and critically ill patients, highlighted by a rapid decline of kidney function occurring a few hours or days after sepsis onset. Systemic inflammation elicited by microbial infections is believed to lead to kidney damage under immunocompromised conditions. However, while AKI has been recognized as a disease with long-term sequelae, partly due to the associated higher risk of chronic kidney disease (CKD), the understanding of kidney pathophysiology at the molecular level and the global view of dynamic regulations in situ after S-AKI, including transition to CKD, remains limited. Existing studies of S-AKI mainly focus on deriving sepsis biomarkers from body fluids. In the present study, we constructed a mid-severity septic murine model using cecal ligation and puncture (CLP), and examined the temporal changes to the kidney proteome and phosphoproteome at day 2 and day 7 after CLP surgery, corresponding to S-AKI and the transition to CKD, respectively by employing an ultrafast and economical filter-based sample processing method combined with the label-free quantitation approach. Collectively, we identified 2,119 proteins and 2,950 phosphosites through multi-proteomics analyses. Here we denote the pathways that are specifically responsive to S-AKI and its transition to CKD, which include regulation of cell metabolism regulation, oxidative stress, and energy consumption in the diseased kidneys. Our data can serve as an enriched resource for the identification of mechanisms and biomarkers for sepsis-induced kidney diseases.

show abstract

The cleavage of gasdermin D by caspase-11 promotes tubular epithelial cell pyroptosis and urinary IL-18 excretion in acute kidney injury

Cited by 169 publications

References 48 publications

circACTR2: A Novel Mechanism Regulating High Glucose-Induced Fibrosis in Renal Tubular Cells <i>via</i> Pyroptosis

circACTR2: A Novel Mechanism Regulating High Glucose-Induced Fibrosis in Renal Tubular Cells <i>via</i> Pyroptosis

<p>Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis</p>

The global proteome and phosphoproteome landscape of sepsis-induced kidney injury

Contact Info

Product

Resources

About