Abstract

ETHNOPHARMACOLOGICAL RELEVANCE Shenfu Decoction (SFD) is a traditional famous prescription for replenishing qi and restoring yang. Pharmacological research has confirmed that SFD can warm and tonify yang qi and exerts good therapeutic effects on cardiovascular-related diseases. However, there are no reports on kidney diseases caused by hypertension, and its molecular mechanism needs further exploration. AIM OF THE STUDY This study aimed to investigate whether SFD ameliorates hypertensive renal disease (HRD) and to clarify whether such protection is achieved through alleviate mitochondrial dysfunction and subsequent inhibition of apoptosis via the AMPK/SIRT1/PGC 1α signaling pathway. METHODS AND MATERIALS Combining network pharmacology, an Ang II-induced hypertensive kidney injury model in C57BL/6 mice, and the NRK-52E cell model, renal function, mitochondrial function, oxidative stress, inflammatory factors, and apoptosis were assessed. Co-immunoprecipitation was used to verify the interaction between SIRT1 and PGC-1α. RESULTS SFD treatment improved AngII-induced renal dysfunction without altering blood pressure. Network pharmacology combined with experiments identified stigmasterol (STI) as the active component, which alleviates mitochondrial dysfunction, reduces oxidative stress/inflammation, and decreases apoptosis by activating the AMPK/SIRT1/PGC-1α pathway. Mechanistically, the N-terminus of SIRT1 can directly interact with the PGC-1α D2 domain. CONCLUSIONS This study provides evidence that SFD and its active STI alleviate HRD by activating the AMPK/SIRT1/PGC-1α pathway to alleviate mitochondrial dysfunction and oxidative stress in renal epithelial cells.