Exploring the mechanism by which modified huangqi chifeng decoction protects podocytes via Arid5a-mediated transcriptional regulation of the AIM2 pyroptosis signaling axis

BackgroundChronic kidney disease (CKD) is a major global health burden with substantial morbidity and mortality. Proteinuria is strongly associated with adverse renal outcomes, and podocyte pyroptosis is increasingly recognized as a key driver of glomerular filtration barrier disruption.ObjectiveThis study sought to elucidate how Modified Huangqi Chifeng Decoction (MHCD) mitigates renal and podocyte injury by modulating the Arid5a/AIM2-dependent pyroptosis pathway.Materials and methodsAn adriamycin-induced nephropathy (ADR) rat model and an in vitro podocyte injury model were established. Twenty-four-hour urinary protein levels, serum biochemical indices, and renal histopathology were assessed. Expression of Arid5a, AIM2, and downstream pyroptosis-related molecules (Caspase-1, ASC oligomerization, GSDMD, IL-1β, and IL-18) was quantified. Mutagenesis of Arid5a binding sites in the AIM2 promoter, along with electrophoretic mobility shift assays (EMSA) and dual-luciferase reporter assays, were used to validate Arid5a’s promoter binding and its transcriptional regulation of AIM2.ResultsMHCD markedly reduced proteinuria, alleviated renal histopathological damage, and improved podocyte viability in ADR rats. These protective effects coincided with downregulation of Arid5a, AIM2, and downstream pyroptosis mediators—including Caspase-1, ASC oligomers, GSDMD, IL-1β, and IL-18. Mechanistically, Arid5a functioned as a transcription factor that binds to the AIM2 promoter to regulate AIM2 expression.ConclusionsMHCD mitigates renal and podocyte injury by suppressing inflammasome activation and pyroptosis through Arid5a-mediated transcriptional activation of the AIM2 signaling axis.