TRAP5 Inhibition Targeting Scar-Associated Macrophages Ameliorates Acute Kidney Injury to Chronic Kidney Disease Transition.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) lacks effective therapies. Using a murine aristolochic acid I model (AAI), followed by a 2 week remodeling phase, we mapped macrophage states across the AKI to CKD transition. Single-cell RNA sequencing of kidneys from control, acute, and remodeling stages profiled 39 345 cells spanning 18 clusters. Macrophage subclustering and trajectories revealed emergence of scar-associated macrophages (SMs) marked by high Acp5 (encoding tartrate-resistant acid phosphatase 5 (TRAP5)) and enriched during the remodeling phase. Cell-cell communication highlighted a dominant Spp1-Cd44 axis driving SM activation. Immunofluorescence confirmed TRAP5+CD68+ macrophage accumulation in multiple murine CKD and human CKD biopsies. Functionally, pharmacological TRAP5 inhibition conferred robust protection against AKI-CKD transition. TRAP5 blockade initiated in the AKI phase markedly attenuated fibrosis, inflammation, and renal dysfunction in both AAI and ischemia-reperfusion injury (IRI) models; while preinhibition similarly mitigated unilateral ureteral obstruction (UUO)-induced fibrosis. In bone marrow-derived macrophages (BMDMs), TRAP5 blockade abrogated osteopontin (Spp1)-driven metabolic and profibrotic reprogramming. In conclusion, TRAP5+ scar-associated macrophages are disease-promoting effectors of maladaptive remodeling in AKI-CKD transition. Targeting TRAP5 not only suppresses profibrotic macrophage activation but also protects renal structure and function across multiple models, establishing TRAP5 inhibition as a promising therapeutic strategy to halt CKD progression.