AMD1-mediated polyamine metabolism governs tubular repair fate by restraining senescence after kidney injury.
AMD1 appears to be a key regulator of tubular repair after acute kidney injury, with its deficiency linked to increased senescence and injury. Spermidine supplementation showed promise in mitigating these effects in a mouse model.
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This study investigated the role of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase 1 (AMD1) in tubular senescence and repair outcomes after acute kidney injury (AKI) using a mouse model. The study found that AMD1 deficiency led to aggravated tubular injury and increased senescence markers, while spermidine supplementation improved renal function and reduced fibrosis. No therapeutic claims are made.
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 (AMD1) regulates tubular senescence and repair outcomes after AKI and elucidated the underlying mechanism. AMD1 dynamics were examined in an ischemia-reperfusion injury model using male C57BL/6J mice by immunofluorescence. AAV-mediated Ksp promoter-driven tubule-specific <i>Amd1</i> conditional knockdown male mice (<i>Amd1</i> <sup>cKD</sup>) were used to assess renal injury, cell-cycle status, senescence, and remodeling, and exogenous spermidine 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 the tubular epithelium, with prominent dynamic induction in proximal tubules early after IRI, but declined to baseline levels during the late phase, representing a relative metabolic insufficiency that correlated inversely with fibrosis. Compared with wild-type controls, <i>Amd1</i> <sup>cKD</sup> mice exhibited aggravated tubular injury, an over two-fold increase in SA-β-gal-positive areas, elevated p21, and reduced Ki67+ proliferation. Conversely, spermidine supplementation improved renal function, reduced fibrosis by 75.3%, and decreased senescent regions by 74%. Mechanistically, AMD1 deficiency increased γH2AX-marked DNA damage and activated the p53/p21 checkpoint, whereas spermidine 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, promote adaptive repair after AKI, and spermidine supplementation represents a potential strategy to mitigate maladaptive AKI-to-CKD progression.