Allograft inflammatory factor-1 in macrophages promotes renal tubular cell epithelial-mesenchymal transition via the NF-κB/IL-1β axis in diabetic kidney disease.

Chronic inflammation and macrophage activation are hallmarks of diabetic kidney disease (DKD). Allograft inflammatory factor-1 (AIF-1), a macrophage-associated inflammatory protein, aggravates high glucose-induced inflammation and oxidative stress in glomerular endothelial cells. However, its pathogenic role in macrophages remains unclear. In the present study, knockdown of AIF-1 by adeno-associated virus (AAV) in db/db mice improved renal function and ameliorated renal histopathological changes, with restored E-cadherin expression and reduced α-SMA expression. Double immunofluorescence staining demonstrated that AIF-1 was predominantly localized in infiltrating macrophages in diabetic kidneys. To explore the underlying mechanisms, THP-1-derived macrophages and a macrophage-tubular epithelial cell coculture system were employed. Under high-glucose conditions, AIF-1 knockdown inhibited NF-κB activation and reduced interleukin-1β (IL-1β) secretion in macrophages, whereas AIF-1 overexpression enhanced both responses. In coculture experiments, AIF-1 overexpression in macrophages promoted epithelial-mesenchymal transition (EMT)-related changes in HK-2 cells, as evidenced by decreased E-cadherin expression and increased α-SMA expression. Neutralization of IL-1β with canakinumab partially reversed the EMT changes induced by AIF-1 overexpression, indicating that IL-1β is a key mediator of macrophage-tubular epithelial cell communication. In conclusion, AIF-1 in macrophages promotes EMT of renal tubular epithelial cells through the NF-κB/IL-1β axis and may represent a potential therapeutic target for DKD.