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

ABSTRACT 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.