Abstract: FR-PO0153
Translocation of GSDMD and RIPK3 to Mitochondria Synergistically Exacerbates Endothelial Injury in Shiga Toxin-Induced Hemolytic Uremic Syndrome
Session Information
- AKI: Mechanisms - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Ye, Keng, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Ma, Huabin, Central Laboratory, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Chen, Zhimin, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
- Xu, Yanfang, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
Background
Hemolytic uremic syndrome (HUS) induced by Shiga toxin (Stx)-producing Escherichia coli (STEC-HUS) is a leading cause of acute kidney injury in children. Characterized by microangiopathic hemolytic anemia, thrombocytopenia, and AKI, STEC-HUS is a form of thrombotic microangiopathy (TMA) where endothelial damage leads to microvascular thrombosis and organ failure. Despite its clinical significance, effective therapies targeting the underlying pathological processes are lacking, and the precise mechanisms by which Stx induces renal and intestinal damage remain unclear. This study investigates the synergistic roles of pyroptosis and necroptosis in the pathogenesis of Stx2-induced HUS.
Methods
HUS was induced by intraperitoneal injection of 1.25 µg/kg Shiga toxin 2. Mice were sacrificed at 0, 24, and 36 hours post-injection, and blood and kidney samples were collected for analysis. Gsdmd−/−, Ripk3−/− and Gsdmd−/−Ripk3−/−mice was used to evaluate the impact of GSDMD and RIPK3 deletion on tubular injury, inflammation, and cell death in HUS model. Stx2-induced mitochondrial dysfunction and cytotoxicity in endothelial cells were also assessed.
Results
We demonstrated that Gsdmd−/−Ripk3−/− mice exhibited significantly enhanced protection against Stx2-induced clinical symptoms, weight loss, and mortality compared to wild-type and single knockout mice. Histological analyses revealed reduced intestinal and renal damage, along with improved renal function and diminished inflammatory cytokine levels. Mechanistically, dual inhibition of pyroptosis and necroptosis markedly decreased thrombus formation and vascular injury, as evidenced by reduced fibrinogen deposition and preserved endothelial integrity. Moreover, Stx2-induced mitochondrial dysfunction and cytotoxicity in endothelial cells were significantly mitigated in Gsdmd−/−Ripk3−/− mice, indicating that both cell death pathways contribute to cellular demise.
Conclusion
Our findings highlight the critical interplay between GSDMD-mediated pyroptosis and RIPK3-mediated necroptosis in driving renal and intestinal injury in HUS. Targeting these pathways may offer a novel therapeutic strategy to mitigate the severity of STEC-HUS and improve clinical outcomes.