Tubular AMD1 preserves polyamine homeostasis, restraining p53/p21 senescence to promote kidney repair after AKI.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a major clinical challenge, often driven by maladaptive repair processes in renal tubular epithelial cells. A key metabolic checkpoint governing tubular cell fate and repair outcomes remains undefined. Cellular senescence, characterized by cell cycle arrest and a pro-inflammatory phenotype, is known to contribute to CKD progression. Understanding the metabolic pathways that regulate senescence and adaptive repair is crucial for developing new therapeutic strategies.

Researchers investigated S-adenosylmethionine decarboxylase 1 (AMD1) dynamics in an ischemia-reperfusion injury (IRI) model using male C57BL/6J mice. They generated AAV-mediated Ksp promoter-driven tubule-specific Amd1 conditional knockdown (Amd1 cKD) male mice to assess renal injury, cell-cycle status, senescence, and remodeling. Exogenous spermidine was administered for rescue experiments. DNA damage signaling and p53/p21 activation were evaluated using immunostaining, Western blotting, and EdU incorporation assays.

AMD1 was predominantly expressed in the tubular epithelium, showing dynamic induction in proximal tubules early after IRI, but declining to baseline levels in the late phase, indicating a relative metabolic insufficiency inversely correlated with fibrosis. Compared with wild-type controls, Amd1 cKD mice exhibited aggravated tubular injury, an over two-fold increase in SA-β-gal-positive senescent areas, elevated p21 expression, and reduced Ki67+ proliferation. Mechanistically, AMD1 deficiency increased γH2AX-marked DNA damage and activated the p53/p21 checkpoint. Conversely, spermidine supplementation significantly improved renal function.

Spermidine reduced fibrosis by 75.3% and decreased senescent regions by 74%, while also attenuating the p53/p21 response and restoring DNA synthesis capacity.