Salvianolic Acid A Protects Against Angiotensin II‐Induced Hypertensive Kidney Disease by Targeting TLR4 and Inhibiting TLR4/Myd88/PI3K/AKT/NF‐κB Pathway

ABSTRACT Hypertensive nephropathy (HN), a significant consequence of chronic hypertension, remains a leading contributor to end‐stage renal disease. Excessive Angiotensin II (Ang II)–driven inflammation, apoptosis, and fibrosis are central to its pathogenesis. Salvianolic acid A (SAA), a polyphenolic compound from Salvia miltiorrhiza , has anti‐inflammatory properties, but its therapeutic potential in HN is unclear. HN was induced in mice by continuous subcutaneous infusion of Ang II (1.44 mg/kg/day) for 28 days. SAA (10 or 20 mg/kg/day) was administered orally every day during the final 14 days. Network pharmacology suggested SAA targets the TLR4/PI3K/AKT/NF‐κB pathway. SAA administration improved renal function and attenuated inflammatory infiltration, tubular cell apoptosis, and interstitial fibrosis, independent of systemic blood pressure. NRK‐52E cells were used in vitro. SAA inhibited PI3K and AKT phosphorylation, suppressed NF‐κB P65 activation, and downregulated pro‐inflammatory cytokines. The PI3K activator 740 Y‐P abolished these effects. Pull‐down, DARTS assays and molecular docking showed interaction between SAA and TLR4, while TLR4 overexpression reversed SAA's protective actions. These findings provide the evidence that SAA exerts protective effects against Ang II‐induced HN, acting through inhibition of the TLR4/MyD88/PI3K/AKT/NF‐κB axis and represents a potential TLR4‐targeted therapy for hypertensive kidney injury.