AMD1-Mediated Polyamine Metabolism Governs Tubular Repair Fate by Restraining Senescence after Kidney Injury

Abstract Failure of adaptive repair after acute kidney injury (AKI) drives the transition to chronic kidney disease (CKD), yet the metabolic checkpoints governing tubular fate remain incompletely defined. Here, we investigated whether the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase 1 (SAMD1/AMD1) regulates tubular senescence and repair outcomes after kidney injury and elucidated the underlying mechanism. Key metabolic pathways and candidate enzymes associated with AKI progression were identified by bioinformatics analyses. AMD1 dynamics were examined in a mouse ischemia–reperfusion injury (IRI) model by immunofluorescence. Proximal tubule–specific Amd1 conditional knockout mice (Amd1cko) were used to assess renal injury, cell-cycle status, senescence, and remodeling, and exogenous spermidine (Spd) was administered for rescue. DNA damage signaling and p53/p21 activation were evaluated by immunostaining/Western blotting and EdU incorporation assays. AMD1 was predominantly expressed in proximal tubules, showed compensatory induction early after IRI, and was markedly downregulated during the late phase, correlating inversely with fibrosis. Compared with wild-type controls, Amd1cko mice exhibited aggravated tubular injury, a two-fold increase in SA-β-gal–positive areas (≈45% vs. ≈20%), elevated p21, and reduced Ki67+ proliferation. Spd supplementation improved renal function (BUN protection rate 71.04%), reduced fibrosis by 75.3%, and decreased senescent regions by ~74%. Mechanistically, AMD1 loss increased γH2AX-marked DNA damage and activated the p53/p21 checkpoint, whereas Spd attenuated this response and restored DNA synthesis capacity. Collectively, tubular AMD1 acts as a metabolic checkpoint that preserves polyamine homeostasis to restrain p53/p21-dependent senescence and promote adaptive repair after AKI, and spermidine supplementation represents a potential strategy to mitigate maladaptive AKI-to-CKD progression.