Paeoniflorin Attenuates the Progression of Diabetic Kidney Disease by Regulating Macrophage Differentiation

ABSTRACT Paeoniflorin (PF), a bioactive compound from Paeonia lactiflora , exhibits anti‐inflammatory and immunomodulatory effects. Macrophage‐driven inflammation is a key contributor to diabetic kidney disease (DKD). This study aimed to determine whether PF mitigates DKD by regulating macrophage polarization. The db/db mice were treated orally with PF (50 or 100 mg/kg/day) for 10 weeks. Renal function, histopathology, and macrophage infiltration were assessed. In vitro, RAW264.7 macrophages were exposed to high glucose. Network pharmacology, molecular docking, cellular thermal shift assays (CETSA), and HIF‐1α siRNA knockdown were used to investigate mechanistic targets. PF improved renal function, reduced albuminuria, and attenuated glomerular injury. It decreased CD68 + macrophage infiltration and inhibited M1 polarization, lowering TNF‐α and iNOS expression. PF directly bound and stabilized HIF‐1α, while HIF‐1α knockdown abolished PF's anti‐inflammatory effects. PF reduced HIF‐1α protein expression without affecting mRNA expression, indicating post‐transcriptional regulation. PF protects against DKD by inhibiting HIF‐1α–mediated M1 macrophage polarization, revealing a novel mechanism to modulate macrophage‐driven renal inflammation and supporting PF as a potential therapeutic agent for DKD.