Myeloid myeloid PRDM16 restrains macrophage inflammatory remodeling and renal fibrosis in diabetic kidney disease by limiting PI3K/AKT activation.

BACKGROUND: Diabetic kidney disease (DKD) is driven by persistent metabolic stress, immune dysregulation and progressive renal fibrosis. PRDM16 is a metabolic transcriptional regulator involved in adipose remodeling, mitochondrial activity and tissue homeostasis, but whether myeloid PRDM16 links diabetic metabolic stress to macrophage polarization and renal fibrosis remains unclear. METHODS: Public DKD transcriptomic datasets were analyzed to identify PRDM16-associated immune and macrophage signatures. Myeloid PRDM16-deficient mice and littermate controls were used to establish experimental DKD. Renal injury, fibrotic remodeling, macrophage polarization and PI3K/AKT signaling were evaluated by histological staining, immunostaining, ELISA, qRT-PCR and western blotting. High glucose-stimulated BMDMs and THP-1-derived macrophages were used for mechanistic validation, and LY294002 was applied to inhibit PI3K/AKT signaling. RESULTS: Bioinformatic analysis linked PRDM16 expression with macrophage-related immune features in DKD. In vivo, myeloid PRDM16 deficiency aggravated renal matrix accumulation, collagen deposition and α-SMA/Collagen-I expression. PRDM16 loss promoted a shift from M2-like macrophages toward M1-like inflammatory macrophages, characterized by increased CD80, CD86, NOS2, TNF-α and IL-1β, together with reduced CD206, Arg1, Fizz1, IL-10 and IL-4. Mechanistically, PRDM16 deficiency enhanced PI3K/AKT phosphorylation in macrophages, whereas LY294002 partially reversed M1-like polarization and attenuated renal inflammation and fibrosis. CONCLUSION: Myeloid PRDM16 acts as a metabolic-immune regulator that restrains M2-to-M1 macrophage polarization and limits renal fibrotic progression in DKD. Loss of PRDM16 aggravates macrophage-driven inflammation and fibrosis partly through PI3K/AKT activation, suggesting that the PRDM16-PI3K/AKT axis may represent a potential target for macrophage-directed intervention in diabetic kidney disease.