Vitamin D alleviates diabetic kidney damage via TREM2-dependent modulation of ferritinophagy and macrophage...

This study aimed to elucidate the renoprotective mechanism of vitamin D (VD) in diabetic kidney disease (DKD), focused on TREM2 signaling, ferritinophagy, and macrophage polarization.

An integrated in vivo and in vitro approach was employed. A DKD rodent model was established using a high-fat diet combined with streptozotocin injections, followed by 10-week intervention with graded doses of vitamin D3 (VitD3). Renal injury was assessed through histopathology, functional assays, and iron deposition quantification. Macrophage polarization and TREM2 expression were profiled by multiplex immunofluorescence and immunoblotting. In parallel, high glucose (HG)-injured RAW264.7 macrophages were used for mechanistic studies. Gain- and loss-of-function experiments with TREM2 siRNA and the ferritinophagy inhibitor 3-MA were applied to dissect the TREM2-ferritinophagy-macrophage polarization axis.

VitD3 supplementation improved systemic metabolism and renal function, attenuated pathological injury, and reduced renal iron deposition in diabetic rats. These improvements were associated with suppressed ferritinophagy and a corrected M1/M2 macrophage balance, linked to TREM2 modulation. In vitro, 1,25(OH)₂D₃ promoted M2 polarization and inhibited ferritinophagy in HG-stimulated macrophages. TREM2 knockdown abolished these effects and exacerbated M1 polarization and iron accumulation. Conversely, inhibition of ferritinophagy enhanced M2 polarization and downregulated TREM2, confirming a functional TREM2-ferritinophagy axis.

VD alleviates diabetic kidney injury by modulating macrophage polarization and ferritinophagy through TREM2. This work provides novel mechanistic insight into VD's immunometabolic actions and supports its potential as an adjunctive therapy for DKD.