Saikosaponin D protects against isoproterenol-induced kidney injury in rats by regulating the intrarenal renin-angiotensin system

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 (AT₁R) 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/AT₁R axis to the protective ACE2/Ang1-7/MasR axis, providing a novel therapeutic target for ISO-related kidney damage.

Intrarenal RAS; Isoproterenol; Kidney injury; Saikosaponin D.