Set 4_S4_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）可引发狭窄肾缺血、肾功能异常及组织损伤，但其致病过程是否由细胞衰老（cellular senescence）介导尚未得到阐明。本研究借助INK-ATTAC转基因小鼠、高分辨率成像技术以及小鼠肾脏的无偏单细胞RNA测序（scRNA-sequencing），明确细胞衰老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致病机制。采用P16特异性干预与广谱槲皮素/达沙替尼干预以抑制细胞衰老，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地位。此外，该致病机制在肾动脉狭窄患者中同样具有保守性。本研究结果揭示了慢性缺血性肾损伤发病的全新机制，并为开发以降低衰老细胞负荷、延缓肾损伤为目标的衰老细胞清除疗法（senolytic therapy）提供了理论支撑。