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.