Set 2_S3_metrics

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、肾功能障碍及组织损伤，但其致病过程是否由细胞衰老介导尚未阐明。本研究采用INK-ATTAC转基因小鼠、高分辨率成像技术及小鼠肾脏的无偏单细胞RNA测序（scRNA-sequencing），作者团队鉴定出细胞衰乃是狭窄后肾脏内肾上皮/基质细胞触发的进行性损伤的重要机制。通过P16特异性干预及广谱的槲皮素/达沙替尼（quercetin/dasatinib）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作用。此外，该致病机制在肾动脉狭窄患者中同样保守存在。本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，并为通过降低衰老细胞负荷以延缓肾损伤的抗衰老疗法（senolytic therapy）的开发提供了理论支撑。