Macrophage FOXO1 Inhibition Protects Against Hyperglycaemia-Associated Kidney Injury

Diabetic kidney disease (DKD) is one of the most significant microvascular complications of diabetes, characterized by high incidence and mortality; however, its pathogenesis remains unclear. Renal inflammation and macrophage infiltration play pivotal roles in driving DKD progression. The transcription factor forkhead box protein O1 (FOXO1) regulates the transcriptional expression of multiple pro-inflammatory molecules and modulates macrophage polarization. Nevertheless, its specific role in DKD macrophages remains unknown. In vivo, streptozotocin-induced DKD mice showed significantly higher FOXO1 expression in infiltrated kidney macrophages. Treatment with the FOXO1-selective inhibitor AS1842856 for 4 or 12 weeks reduced serum creatinine, blood urea nitrogen, renal matrix collagen deposition and the severity of macrophage infiltration in DKD mice. In vitro, using mouse bone marrow-derived macrophages and RAW264.7 cells cultured under high glucose, we found that high glucose promoted pro-inflammatory M1 macrophage polarization. This polarization process was effectively blocked by either AS1842856 treatment or FOXO1 small interfering RNA-mediated gene silencing. In summary, FOXO1 critically regulates macrophage infiltration and functional phenotype in DKD-affected renal tissue. Targeting FOXO1 therefore holds promise as a potential therapeutic strategy to delay DKD progression.