Naringenin inhibited vascular calcification and attenuated senescence-associated changes through the p53/TOP2Aaxis

BACKGROUND: Vascular calcification (VC) is a major cardiovascular complication of chronic kidney disease (CKD). Senescence-associated vascular changes have been increasingly implicated in CKD-related VC. Naringenin, a natural flavonoid with anti-oxidative and anti-inflammatory properties, has shown protective effects in several age-related disorders, but its role and mechanism in CKD-associated VC remain unclear. METHODS: Human vascular specimens, high-Pi-induced vascular smooth muscle cells (VSMCs), and an adenine/high-phosphate-induced rat model of CKD-associated VC were used to evaluate the relationship between calcification and senescence-associated changes and to assess the effects of naringenin. Histological staining, SA-β-Gal staining, Western blotting, immunofluorescence, immunohistochemistry, RNA sequencing, molecular docking, chromatin immunoprecipitation, and dual-luciferase assays were performed to explore the possible mechanism. RESULTS: VC was positively associated with senescence-associated changes in patient tissues, cultured VSMCs, and rat aortas. Naringenin significantly reduced calcium deposition and attenuated senescence-associated marker changes both in vitro and in vivo. Transcriptomic analysis implicated the p53 pathway and identified TOP2A as a downstream effector associated with naringenin treatment. Mechanistically, naringenin was associated with suppression of p53 signaling, relief of p53-mediated transcriptional repression of TOP2A, and restoration of TOP2A expression. Functional assays further suggested that p53 activation or TOP2A knockdown attenuated the protective effects of naringenin. CONCLUSION: Naringenin inhibits vascular calcification by modulating the p53/TOP2A axis, and this protective effect is accompanied by attenuation of senescence-associated changes. These findings support naringenin as a mechanistically relevant candidate for CKD-associated vascular calcification, although the upstream mechanism underlying p53 suppression remains to be clarified.