Nicotinamide riboside alleviates sepsis-induced acute kidney injury by suppressing ferroptosis

Sepsis-induced acute kidney injury (SAKI) is the predominant type of acute kidney injury encountered in intensive care units. Nicotinamide riboside (NR) improves kidney function in acute and chronic kidney diseases; however, its role in SAKI and the underlying mechanism remain unclear. We aimed to investigate the inhibitory effects of NR on Ferroptosis in SAKI and explored the potential mechanisms involved. Cecal ligation and puncture markedly reduced SIRT1 expression in vivo, impaired renal function, decreased glutathione (GSH) activity, and Glutathione Peroxidase 4 (GPX4) expression, and increased the expression levels of acyl-CoA synthetase long-chain family member 4 (ACSL4), ferritin heavy chain (FTH), and 4-hydroxynonenal (4-HNE). Pretreatment with NR ameliorated these changes, whereas the protective effects of NR were reversed by treatment with the selective SIRT1 Inhibitor, EX527. NR promoted SIRT1 expression in vitro and restored lipopolysaccharide (LPS)-induced downregulation of GPX4 and upregulation of ACSL4, FTH, and 4-HNE in human renal tubular epithelial (HK-2) cells. Meanwhile, NR treatment increased GSH activity and reduced the production of Reactive Oxygen Species. EX527 treatment or SIRT1 knockdown abolished the NR-mediated Ferroptosis alleviation in vitro. Additionally, we discovered that SIRT1 overexpression mimicked the protective function of NR in inhibiting Ferroptosis in LPS-stimulated HK-2 cells. In light of our study findings, we concluded that NR suppressed Ferroptosis by upregulating SIRT1 expression, thereby mitigating AKI induced by sepsis. This study provides a foundation for further research on SAKI and identifies potential therapeutic targets. KEY MESSAGES: NR ameliorated sepsis-induced acute kidney injury by suppressing Ferroptosis. NR attenuated SIRT1 expression, resulting in Ferroptosis inhibition. Using EX527 or SIRT1 knockdown abolished NR-mediated Ferroptosis alleviation. SIRT1 overexpression mimicked NR's protective function in inhibiting Ferroptosis.

Acute kidney injury; Ferroptosis; Nicotinamide riboside; SIRT1; Sepsis.