Daphnetin Alleviates Sepsis-Associated Acute Kidney Injury by Promoting Autophagy and Suppressing Non-canonical NF-κB Signaling.

Background

Sepsis-Associated Acute Kidney Injury (SA-AKI) is a lifethreatening complication with high mortality and limited treatment options. Daphnetin (DAP), a coumarin derivative with anti-inflammatory activity, has shown promise in several inflammatory disorders, but its role in SA-AKI remains unclear.

Methods

We induced SA-AKI in mice using the Cecal Ligation and Puncture (CLP) model and established an in vitro injury model by stimulating HK-2 cells with Lipopolysaccharide (LPS). The effects of DAP were evaluated in both models. RNA sequencing was performed to identify the mechanisms underlying DAP-mediated protective effects, and the results were further validated by immunoblotting and related assays.

Results

DAP treatment markedly reduced renal injury, lowered serum creatinine and blood urea nitrogen levels, preserved renal histological architecture, and attenuated tubular cell apoptosis. It also reduced the production of pro-inflammatory cytokines and enhanced autophagic activity. Transcriptomic analysis together with biochemical validation implicated non-canonical nuclear factor kappa-B (NF-κB) signaling as a potential mediator of the anti-inflammatory effects of DAP. In addition, DAP reduced pro-inflammatory M1 macrophage infiltration in the kidney.

Discussion

These findings expand current understanding of the mechanisms underlying DAP-mediated renoprotection by demonstrating enhanced autophagic activity in experimental SA-AKI. The observation that pharmacological inhibition of NF-κB-inducing kinase (NIK) also enhances autophagic activity suggests that suppression of non-canonical NF-κB signaling contributes to autophagy regulation. Together with its anti-inflammatory effects, these findings support a multifaceted mechanism underlying the renoprotective actions of DAP.

Conclusion

DAP attenuates inflammation and kidney injury in SA-AKI, accompanied by inhibition of non-canonical NF-κB signaling and enhanced autophagic activity. These findings suggest that DAP may represent a promising therapeutic candidate for SAAKI.