Spermidine alleviates sepsis-induced acute kidney injury by suppressing apoptosis and inflammation through modulation of TLR4-mediated signaling

Oct 1, 2025The Journal of toxicological sciences

Spermidine may reduce sepsis-related kidney damage by lowering cell death and inflammation through controlling TLR4 signaling

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Abstract

Spermidine treatment at concentrations of 25-100 μM significantly mitigated renal damage in sepsis-associated acute kidney injury models.

Spermidine improved functional kidney markers, such as blood urea nitrogen and serum creatinine.
The treatment reduced oxidative stress by enhancing antioxidant enzyme activities and decreasing lipid peroxidation in kidney tissues.
Spermidine lowered apoptosis rates in kidney cells, as shown by decreased apoptotic markers and caspase activation.
Inhibition of inflammatory cytokine production was observed with spermidine, associated with the modulation of the TLR4/MyD88/NF-κB signaling pathway.
These effects suggest that spermidine may alleviate sepsis-induced acute kidney injury through combined actions on apoptosis and inflammation.

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Sepsis-associated acute kidney injury (AKI) remains a critical clinical challenge with limited therapeutic options. This study investigated the renoprotective effects of spermidine using sepsis-associated AKI models. In vitro, HK-2 cells were challenged with lipopolysaccharide (LPS) to establish an inflammatory injury model, followed by spermidine treatment (25-100 μM). In vivo, a cecal ligation and puncture (CLP)-induced septic AKI mouse model was employed. Key methodologies included CCK-8 viability assay, flow cytometry apoptosis analysis, western blotting (apoptotic proteins: Bcl-2/Bax/cleaved caspase-9; TLR4/MyD88/TRAF6/p-p65), ELISA (TNF-α/IL-6/IL-1β), TUNEL staining, and histopathological assessment, with spermidine doses of 25-100 μM (cells) and 50 mg/kg (mice). We found that spermidine treatment significantly mitigated renal histopathological damage and improved functional markers, including blood urea nitrogen, serum creatinine, and neutrophil gelatinase-associated lipocalin. Spermidine administration attenuated oxidative stress by restoring antioxidant enzyme activities while reducing lipid peroxidation in renal tissues. Spermidine suppressed apoptosis in both LPS-challenged HK-2 and CLP-injured kidneys, evidenced by reduced apoptotic markers and caspase activation. Furthermore, spermidine inhibited systemic and intrarenal inflammatory cytokine production through modulation of the TLR4/MyD88/NF-κB signaling axis. These findings collectively establish that spermidine alleviates sepsis-induced AKI through coordinated suppression of apoptosis and inflammation mediated by TLR4/MyD88/NF-κB pathway inhibition.

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Spermidine alleviates sepsis-induced acute kidney injury by suppressing apoptosis and inflammation through modulation of TLR4-mediated signaling

Abstract

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