Set 1_S2_web_summary

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）可引发狭窄肾缺血、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。本研究借助INK-ATTAC转基因小鼠、高分辨率成像技术及小鼠肾脏的无偏scRNA测序，鉴定出细胞衰乃是狭窄后肾脏内肾上皮/基质细胞发生进行性损伤的重要机制。无论是靶向P16的特异性干预手段，还是广谱的槲皮素/达沙替尼抗衰老干预，均可有效抑制细胞衰老，进而改善肾脏功能与组织结构，这一结果凸显了细胞衰老在该病发病机制中的核心作用。进一步研究表明，该致病机制在RAS患者体内同样具有保守性。上述研究揭示了慢性缺血性肾损伤发病机制中的全新路径，并为通过衰老细胞清除疗法（senolytic therapy）减轻衰老细胞负荷、延缓肾损伤提供了理论依据。