molecule_info.h5

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、功能障碍与损伤，但其致病过程是否由细胞衰老（cellular senescence）介导，目前尚未阐明。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倚单细胞RNA测序（scRNA-sequencing），研究团队发现细胞衰老乃是狭窄后肾脏内肾上皮/基质细胞所触发的进行性损伤的重要机制。无论是p16特异性（p16-specific）干预，还是槲皮素（quercetin）/达沙替尼（dasatinib）这两类广谱性衰老抑制手段，均可改善肾脏功能与结构，进一步突显了细胞衰老在该病发病机制中的核心作用。此外，该衰老介导的致病机制在RAS患者中同样保守存在。本研究揭示了慢性缺血性肾损伤发病机制中的全新通路，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依据。