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

Abstract

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.