Salvianolic acid C protects against sepsis-associated acute kidney injury through promotion of PGC1α-mediated renal gluconeogenesis.

BACKGROUND

Sepsis-associated acute kidney injury (SA-AKI) remains a critical clinical challenge with no effective targeted therapies available.

PURPOSE: This study aimed to investigate the therapeutic potential of salvianolic acid C (SAC) in SA-AKI and elucidate its underlying molecular mechanisms.

METHODS

SA-AKI models were established in renal cells and mice via LPS stimulation. RNA sequencing was performed to dissect the downstream mechanisms of SAC in SA-AKI. The downstream mechanisms were validated by qPCR, Western blotting, molecular docking, immunohistochemical staining, surface plasmon resonance, and cellular thermal shift assay.

RESULTS

Administration of SAC significantly improved renal function, alleviated tubular injury, suppressed renal inflammation in septic mice. Consistent with these findings, SAC exhibited potent anti-inflammatory effects in LPS-treated renal tubular epithelial cells. RNA sequencing identified gluconeogenesis as a significantly enriched pathway modulated by SAC treatment, which was further validated at mRNA, protein and metabolic levels. The critical role of renal gluconeogenesis in SA-AKI was confirmed through genetic deletion or overexpression of the gluconeogenic enzyme PCK1 in both renal cells and mouse kidneys. Notably, PCK1 deletion abolished SAC-mediated protection in SA-AKI models. Further experiments revealed that SAC restored renal gluconeogenesis through directly binding to and upregulating PGC1α. Mechanistic studies showed that SAC treatment reduced histone H3 lysine 18 lactylation-mediated inflammatory responses in SA-AKI, an effect dependent on PCK1 activity and reversed by lactate supplementation.

CONCLUSION

Our findings uncover a novel PGC1α-gluconeogenesis-histone lactylation axis through which SAC protects against SA-AKI, thereby highlighting metabolic regulation as a promising therapeutic strategy for SA-AKI.