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Gasdermin E Deletion Attenuates Ureteral Obstruction- and 5/6 Nephrectomy-Induced Renal Fibrosis and Kidney
Mengying Wu1,2,3, Weiwei Xia1,2,3, Qianqian Jin1,2,3
1Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
Abstract:
Renal fibrosis contributes to kidney dysfunction in various chronic kidney diseases (CKDs). Renal fibrosis can be driven by renal tubular cell death and inflammation. Deletion of gasdermin E (GSDME), an executor of pyroptosis, has been reported to suppress renal tubular cell pyroptosis in several models of kidney injury. However, additional evidence confirming the role of GSDME in regulating renal fibrosis and kidney function in different CKDs is required. In our study, N-GSDME expression was significantly elevated in CKD models in vivo and in vitro. GSDME deletion alleviated renal fibrosis and inflammation in both unilateral ureteral ligation (UUO) and 5/6 nephrectomy (5/6Nx) models along with the attenuation of renal dysfunction. N-GSDME overexpression had a detrimental effect on fibrotic responses in UUO kidneys and TGF-β1-treated renal tubular epithelial cells. In addition, administration of caspase-3 inhibitor Z-DEVD-FMK, which inhibits caspase-3-mediated GSDME cleavage, protected against renal fibrosis both in vivo and in vitro. Collectively, these results provide evidence that the activation of GSDME is critical in regulating both renal fibrosis and kidney dysfunction possibly via promoting inflammatory responses in CKD. These findings may offer new insights into the identification of new therapeutic targets for protecting against CKDs.
Insights
Gasdermin E (GSDME) activation drives kidney fibrosis and dysfunction in chronic kidney diseases (CKDs). Inhibiting GSDME protects kidney function and reduces fibrosis, offering new therapeutic targets.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- Renal fibrosis is a key factor in chronic kidney disease (CKD) progression, often linked to renal tubular cell death and inflammation.
- Gasdermin E (GSDME), a pyroptosis executor, has shown potential in mitigating kidney injury, but its specific role in CKD-associated fibrosis requires further investigation.
Purpose of the Study:
- To investigate the role of Gasdermin E (GSDME) in regulating renal fibrosis and kidney function across different chronic kidney disease (CKD) models.
- To explore the therapeutic potential of targeting GSDME in the context of renal fibrosis and dysfunction.
Main Methods:
- Assessed N-GSDME expression in *in vivo* (unilateral ureteral ligation and 5/6 nephrectomy) and *in vitro* (TGF-β1-treated renal tubular epithelial cells) CKD models.
- Examined the effects of *GSDME* deletion and N-GSDME overexpression on renal fibrosis, inflammation, and kidney function.
- Utilized a caspase-3 inhibitor (Z-DEVD-FMK) to block GSDME cleavage and evaluated its protective effects.
Main Results:
- N-GSDME expression was significantly upregulated in CKD models.
- *GSDME* deletion attenuated renal fibrosis, inflammation, and dysfunction in both UUO and 5/6Nx models.
- Overexpression of N-GSDME exacerbated fibrotic responses, while caspase-3 inhibition demonstrated protective effects against renal fibrosis.
Conclusions:
- GSDME activation plays a critical role in promoting renal fibrosis and kidney dysfunction in CKD, likely through inflammatory pathways.
- Targeting GSDME presents a promising therapeutic strategy for mitigating renal fibrosis and preserving kidney function in chronic kidney diseases.
