Set 1_S2_raw_gene

Renal artery stenosis (RAS) engenders stenotic-kidney ischemia, dysfunction, and injury, but whether these are mediated by cellular senescence has not been elucidated. Using INK-ATTAC transgenic mice, high-resolution imaging, and unbiased scRNA-sequencing of murine kidneys, the authors identified cellular senescence as an important mechanism of progressive injury triggered in renal epithelial/stromal cells within post-stenotic kidneys. Both P16-specific and broad quercetin/dasatinib interventions to blunt senescence improved renal function and structure, underscoring its central role in the pathogenesis of the disease. Furthermore, this mechanism was conserved in human subjects with RAS. These observations reveal new mechanisms that contribute to the pathogenesis of chronic ischemic renal injury, and support development of senolytic therapy to reduce senescent cell burden and delay renal injury.肾动脉狭窄（renal artery stenosis, RAS）可引发患侧肾脏缺血、功能异常与组织损伤，但其致病过程是否由细胞衰老（cellular senescence）介导尚未阐明。本研究团队借助INK-ATTAC转基因小鼠模型、高分辨率成像技术及小鼠肾脏的无偏单细胞RNA测序（scRNA-sequencing），明确细胞衰乃是狭窄术后肾脏内肾上皮细胞/基质细胞发生进行性损伤的重要致病机制。采用靶向P16的特异性干预手段与槲皮素/达沙替尼的广谱抗衰老干预，均可改善肾脏功能与组织结构，这进一步凸显了细胞衰老在该病发病机制中的核心作用。此外，该致病机制在肾动脉狭窄患者中同样具有保守性。本研究揭示了慢性缺血性肾损伤发病机制中的全新环节，并为开发衰老细胞清除疗法（senolytic therapy）以减轻衰老细胞负荷、延缓肾损伤提供了理论支撑。