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CHOP-mediated Gasdermin E expression promotes pyroptosis, inflammation, and mitochondrial damage in renal ischemia-reperfusion injury.
Cell Death & Disease 2024 Februrary 23
In clinical practice, renal ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), often leading to acute renal failure or end-stage renal disease (ESRD). The current understanding of renal IRI mechanisms remains unclear, and effective therapeutic strategies and clear targets are lacking. Therefore, the need to find explicit and effective ways to reduce renal IRI remains a scientific challenge. The current study explored pyroptosis, a type of inflammation-regulated programmed cell death, and the role of Gasdermins E (GSDME)-mediated pyroptosis, mitochondrial damage, and inflammation in renal IRI. The analysis of human samples showed that the expression levels of GSDME in normal human renal tissues were higher than those of GSDMD. Moreover, our study demonstrated that GSDME played an important role in mediating pyroptosis, inflammation, and mitochondrial damage in renal IRI. Subsequently, GSDME-N accumulated in the mitochondrial membrane, leading to mitochondrial damage and activation of caspase3, which generated a feed-forward loop of self-amplification injury. However, GSDME knockout resulted in the amelioration of renal IRI. Moreover, the current study found that the transcription factor CHOP was activated much earlier in renal IRI. Inhibition of BCL-2 by CHOP leaded to casapse3 activation, resulting in mitochondrial damage and apoptosis; not only that, but CHOP positively regulated GSDME thereby causing pyroptosis. Therefore, this study explored the transcriptional mechanisms of GSDME during IRI development and the important role of CHOP/Caspase3/GSDME mechanistic axis in regulating pyroptosis in renal IRI. This axis might serve as a potential therapeutic target.
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