Salvianolic acid C alleviates acute kidney injury by restoring fructose-1,6-bisphosphatase 1-mediated gluconeogenesis

This research was targeted to investigate the pharmacological effects and mechanisms of Salvianolic acid C (SAC), a natural compound extracted from the Chinese traditional herbal Danshen (<i>Salviae Miltiorrhizae Radix et Rhizoma</i>), in acute kidney injury (AKI). Male C57BL/6J mice were used to create animal models and SAC (10 mg/kg, i.p.) or saline was administered 24 h before modeling. In both ischemia reperfusion injury (IRI) induced AKI and cisplatin (Cis) induced AKI models, SAC significantly alleviated the decline of renal function and destruction of renal pathological structure, which were correlated with reduced expression of renal injury markers and inhibited renal cell apoptosis. Non-targeted metabolomics sequencing revealed that the gluconeogenesis pathway was downstream of the renal protective effect of SAC in AKI. Further experiments revealed that the expression of key gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) was significantly decreased in AKI kidneys. AKI induced the reduction in glucose levels from serum and increase in lactate levels from serum and renal tissue. All of these metabolic changes were improved after the SAC treatment. The protective effects of SAC were reversed by an FBP1 inhibitor. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and forkhead box O1 (FOXO1), identified as gluconeogenesis promoting factor, were decreased after injection of cisplatin, which were reversed by SAC. Finally, molecular docking and SPR experiments revealed the direction interaction between FBP1 and SAC. Collectively, SAC possibly exerts its effect through a dual regulatory mechanism: by modulating the FOXO1/PGC1α/FBP1 signaling axis and <i>via</i> direct interaction with FBP1.