Abstract

Saikosaponin D (SSD), a triterpene saponin isolated from Bupleurum falcatum , exhibits diverse pharmacological activities and has been shown to alleviate kidney-related diseases in rodent models. However, its effects on isoproterenol (ISO)-induced kidney injury and the underlying mechanisms have not been fully elucidated. Herein, SSD administration effectively mitigated ISO-induced kidney injury in Sprague-Dawley rats, as evidenced by improvements in renal function parameters (e.g., reduced plasma creatinine and blood urea nitrogen) and histopathological structure. Specifically, SSD significantly suppressed ISO-induced upregulation of inflammatory cytokines, fibrotic markers, and kidney injury biomarkers in renal tissues. SSD treatment downregulated renal expression of angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), reduced renal ACE activity and urinary angiotensin II (AngII) excretion, and upregulated renal angiotensin-converting enzyme 2 (ACE2) activity (without altering its expression) while increasing urinary angiotensin 1–7 (Ang1–7) excretion. Notably, no significant changes in plasma AngII or Ang1–7 concentrations were observed, indicating SSD specifically modulates the intrarenal renin-angiotensin system. Functional validation experiments showed that co-administration of SSD with the ACE inhibitor enalapril or AngII type 1 receptor (AT 1 R) antagonist losartan further potentiated its protective effects against ISO-induced kidney injury. In contrast, co-treatment with the ACE2 inhibitor MLN-4760 or Mas receptor (MasR) antagonist A779 completely abrogated SSD's renoprotective effects. In conclusion, our findings demonstrate that SSD exerts renoprotective effects against ISO-induced kidney injury by inhibiting renal fibrosis and inflammation. Mechanistically, SSD shifts the intrarenal RAS balance from the pro-inflammatory/fibrotic ACE/AngII/AT 1 R axis to the protective ACE2/Ang1–7/MasR axis, providing a novel therapeutic target for ISO