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FDX1-mediated disulfidptosis drives progression of sepsis-associated AKI

ABSTRACT: Renal tubular epithelial cells are damaged in sepsis-associated acute kidney injury (S-AKI). In acute kidney injury (AKI) caused by ischemia, toxins and inflammatory factors, various forms of cell death are induced. In this study, we investigated the role and mechanism of disulfidptosis in the pathophysiological processes of S-AKI. NADPH was significantly downregulated in S-AKI mice, and closely involved in the occurrence of disulfidptosis. Interestingly, in the kidney tissues and cells of S-AKI mice, the disulfidptosis marker was significantly upregulated, actin cytoskeletal disulfide bond was formed, and cytoskeletal morphology contracted. Mechanistical studies showed that specific deletion of FDX1 in mouse kidney tissues and human renal tubular epithelial cells (HK-2) inhibited disulfidptosis and alleviated kidney injury in S-AKI. This was also demonstrated in HK-2 cell injury induced by the serum from children with sepsis. In addition, activating G6PD using G6PD agonist AG1 also significantly attenuated disulfidptosis and ameliorated renal injury. These findings suggest that FDX1 interacts with G6PD to induce NADPH depletion in renal tubular epithelial cells, thus activating disulfidptosis to exacerbate S-AKI. Blocking FDX1 through genetical or pharmacological methods may serve as a potential strategy against S-AKI.

ORGANISM(S): Homo sapiens

PROVIDER: GSE347117 | GEO | 2026/09/30

REPOSITORIES: GEO

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Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.

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FDX1-mediated disulfidptosis drives progression of sepsis-associated AKI

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