Lithospermic acid regulates macrophage polarization via AMPKα1 activation and ameliorates sepsis associated acute kidney injury in mice.

Abstract

Sepsis is a systemic inflammatory response syndrome resulted from severe infection. Macrophage polarization plays an important role in sepsis associated acute kidney injury (SA-AKI). Lithospermic acid (LA) is a phenolic acid isolated from Salvia miltiorrhiza and exerts an anti-inflammatory effect in multiple inflammatory diseases; however, the role of LA in SA-AKI remains unknown. This study investigates the therapeutic potential of LA in SA-AKI by targeting macrophage polarization. We demonstrate that LA significantly increased survival, attenuates kidney injury and renal inflammation in SA-AKI mice. Besides, LPS-activated RAW 264.7 cells and THP-1 cells were established to further explore underlying mechanism of LA. Our finding discovered that LA suppresses M1 macrophage polarization and the release of inflammatory cytokines and ROS. Further mechanistic studies reveal that LA activated AMP-activated protein kinase alpha1 (AMPKα1), leading to inhibit the expression of p-mTOR (Ser2448) and p-NF-κB (Ser536). Furthermore, AMPKα1 silencing abolishes the inhibitory effects of LA on M1 macrophage polarization and inflammation. Taken together, the anti-inflammatory effect of LA in SA-AKI was associated with the AMPKα1/mTOR/NF-κB pathway-mediated macrophage polarization. Our study provides a constructive mechanistic basis to endorse the therapeutic potential of LA in anti-inflammatory diseases, such as SA-AKI.