Set 1_R1_filtered_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）介导尚未阐明。本研究团队借助INK-ATTAC转基因小鼠、高分辨率成像技术，以及针对小鼠肾脏的无偏单细胞RNA测序（scRNA-sequencing），鉴定出细胞衰老是狭窄后肾脏内肾上皮/基质细胞所触发的进行性肾损伤的重要机制。采用P16特异性干预手段与广谱的槲皮素/达沙替尼（quercetin/dasatinib）衰老抑制方案，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，该致病机制在人类RAS患者中同样保守存在。上述研究结果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）以降低衰老细胞负荷、延缓肾损伤提供了理论支撑。