Inhibiting SIRT2 attenuates sepsis-associated acute kidney injury via NEU1 acetylation-mediated CD44/PI3K/AKT pathway activation.

AIMS: Sepsis-associated acute kidney injury (S-AKI) is a severe complication of sepsis, characterized by high morbidity and mortality, yet lacks effective treatment options in clinical practice. This study aims to investigate the role of SIRT2 in mediating renal injury and inflammation in S-AKI.

MATERIALS AND

METHODS

LPS-induced S-AKI models were established in wild-type and SIRT2 whole-body knockout mice, as well as in HK-2 cells with SIRT2 knockdown or overexpression. Renal injury, inflammatory cytokines, macrophage infiltration, and cell death were evaluated by histological, biochemical, and molecular analyses. NEU1 acetylation, sialidase activity, CD44 sialylation, and downstream PI3K/AKT signaling were further examined. Pharmacological inhibition studies in mice were performed using SIRT2 selective inhibitor AGK2 and a nano-formulation of AGK2 (Nano-AGK2).

KEY FINDINGS: We found that SIRT2 whole-body knockout significantly alleviated renal damage and reduced pro-inflammatory cytokines in S-AKI. Knockdown of SIRT2 attenuated LPS-induced inflammation and cell death in HK-2 cells, whereas its overexpression exacerbated the inflammatory response and cell death. Mechanistically, SIRT2 was shown to deacetylate NEU1 at lysine 395. Inhibiting SIRT2 caused hyperacetylated NEU1, which reduced NEU1 sialidase activity and enhanced CD44 sialylation and CD44/HA binding, promoting PI3K/AKT signaling and renal protection. Furthermore, pharmacological inhibition using AGK2 mitigated LPS-induced renal injury and inflammation, while Nano-AGK2 exhibited enhanced renal accumulation and therapeutic efficacy compared to free AGK2.

SIGNIFICANCE: These findings identify SIRT2 as a novel post-translational regulator in S-AKI, suggesting that SIRT2 inhibition may serve as a potential therapeutic target for S-AKI, which deserves further preclinical investigation.