Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy

BACKGROUND Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescence and their temporal pattern remain unknown. METHODS AND RESULTS Chronic renal ischemia was induced in transgenic INK-ATTAC mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage assessed. Selective clearance of highly p16Ink4a-expressing cells using intraperitoneal AP20187 starting 1, 2, or 4 weeks after RAS attenuated cellular senescence and improved stenotic-kidney function, whereas starting immediately after RAS induction was unsuccessful. Broader clearance of senescent cells using the oral senolytic combination Dasatinib and Quercetin in C57BL/6 RAS mice was more effective in clearing p21 (Cdkn1a)-positive cells and alleviating renal dysfunction and damage. Unbiased single-cell RNA-sequencing in freshly-dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. Like mice, injured human stenotic kidneys exhibited cellular senescence, suggesting that this process is conserved. CONCLUSIONS Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury.