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

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.

Acute kidney injury; Apoptosis; Inflammation; Sepsis; Spermidine; TLR4/MyD88/NF-κB.