TREM2-Expressing Macrophages Linked to Compartment-Specific Protection in Experimental Diabetic Kidney Disease

A study in the Journal of the American Society of Nephrology examined whether macrophage origin and location influence TREM2-associated protection in diabetic kidney disease. Researchers integrated single-cell RNA sequencing and spatial transcriptomics of diabetic OVE26 kidneys with reciprocal bone marrow transplantation in a high-fat diet plus streptozotocin-induced diabetic model. Outcomes included glomerular hypertrophy, tubulointerstitial injury, lipid accumulation and apoptotic cell clearance.

Global TREM2 deficiency exacerbated glomerular hypertrophy and tubulointerstitial injury. Spatial analyses identified two TREM2-expressing populations: Mrc1-positive kidney-resident macrophages around glomeruli and Ccr2-positive monocyte-derived macrophages infiltrating the tubulointerstitium. TREM2 loss reduced phagosome and endocytic pathway activity and impaired clearance of apoptotic debris and lipid aggregates, particularly in the tubulointerstitium.

Transplantation experiments suggested that recipient-resident TREM2 was more closely associated with preserved glomerular structure, whereas donor-derived hematopoietic TREM2 was more strongly associated with reduced tubular lipid accumulation, apoptotic tubular epithelial cells and tubulointerstitial injury. These findings support compartment-specific protective functions but do not establish a therapeutic benefit in patients. The supplied report provides neither sample sizes nor numerical effect estimates, limiting assessment of the magnitude and precision of the findings.