Abstract

Background Cardiorenal syndrome is driven by detrimental heart-kidney crosstalk, where inflammation is a pivotal mediator. However, specific therapies to block this pathological organ communication are still lacking. Salvia miltiorrhiza ( S. miltiorrhiza ) has emerged as a promising multi-target therapeutic candidate, yet its mechanistic role within the cardiorenal network remains largely unexplored. Purpose This study aimed to investigate aqueous extract of S. miltiorrhiza root as a potential treatment for Cardiorenal syndrome by targeting the inflammatory axis between the heart and kidneys. Methods We employed multiple murine models including myocardial infarction, renal ischemia-reperfusion, adenine-induced nephropathy, and a novel dual-injury (myocardial infarction + adenine) model. Cardiac and renal functions were assessed through echocardiography, histological analysis, and serum biomarkers. In vitro studies using neonatal rat cardiomyocytes and renal tubular cells examined the NEU1-TLR4-IL-1β pathway through ChIP-qPCR, co-culture systems, and receptor blockade approaches. Results Aqueous extract of S. miltiorrhiza root demonstrated no direct effect on adenine-induced kidney injury but significantly ameliorated both cardiac and renal damage in the composite cardiorenal injury model, indicating indirect renoprotection via the cardiorenal axis. Mechanistically, salvianolic acid B, the primary active constituent, directly targeted NEU1 in cardiomyocytes, inhibiting NEU1-mediated TLR4 transcription and subsequent IL-1β release. This disruption of IL-1β-mediated cardiorenal cross-talk ultimately protected against kidney injury. Conclusion Salvianolic acid B alleviates kidney injury by suppressing myocardial NEU1 to block pro-inflammatory cross-talk. These findings provide a key mechanistic insight into the cardiorenal protection offered by S. miltiorrhiza .