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

Abstract

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.

Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation

“…These results extended the potential of targeting GSDME in treating different types of AKI. A recently conducted study also provided evidence that GSDME promoted diabetic kidney disease by triggering pyroptosis, which is consistent with our results 34 . The role of FL-GSDME and its cleaved form was also determined in human TECs.…”

LncRNA FOXD3-AS1/miR-135a-5p function in nasopharyngeal carcinoma cells

“…In this study, knockdown of FOXD3-AS1 attenuated C666-1 cell proliferation and improved cell apoptosis. Many targets exert functions in tumorigenesis and development of diseases by influencing signal pathways and regulating genes, such as Caspase-3, which directly influenced cell apoptosis [38]. Similar results were observed in this research: FOXD3-AS1-siRNA promoted Caspase-3 activity, enhanced cleaved-Caspase3 levels, and suppressed pro-Caspase3 expression.…”

Gasdermin E-mediated programmed cell death: An unpaved path to tumor suppression

“…Despite adverse reactions, such as CRS 55 , severe weight loss upon chemotherapy 13 , and induction of renal tubulointerstitial fibrosis progression 82 , the significant anti-tumor potential of GSDME should not be ignored. Some researchers propose that GSDME may be a promising biomarker for cancer detection, for predicting the 5-year patient survival rate 83 , and for use in GSDME-mediated PCD initiated immunogenic cell death (ICD) in GSDME-overexpressing cells 54 .…”