Senolytics for kidney repair

Abstract

0123456789();: Nature reviews | Nephrology ageing and chronic kidney disease (CKD) have long been associated with increased susceptibility to kidney injury and impaired postinjury repair. senescent cells are promising therapeutic targets to boost kidney recovery after injury, according to a new study by Katie Mylonas, David Ferenbach and colleagues. the presence of senescent cells has been associated with ageing-related kidney impairment and the researchers found that levels of markers of permanent cell cycle arrest, such as CKDN1A, were higher in diseased kidneys than in healthy control tissue; CKDN1A levels also increased with age. accordingly, older mice expressed higher levels of genes associated with senescence and had more kidney fibrosis following unilateral ischaemia– reperfusion injury (iri) than younger mice. treatment with the senolytic drug aBt-263 prior to iri efficiently reduced the number of senescent cells and ameliorated the fibrotic phenotype in older mice. This improvement in fibrosis was accompanied by a reduction in the expression of transforming growth factor β1 and in the number of profibrotic CD206+ macrophages compared with untreated controls; lower serum cystatin C levels in treated animals suggest that the drug also improved kidney function. Having demonstrated that γirradiation can induce senescence in the kidneys of young animals and exacerbates postiri fibrosis, the researchers tested whether aBt-263 could also protect the kidneys of young animals with irradiationinduced senescence from iri. “the treatment reduced senescent cell numbers and restored a regenerative phenotype in the kidneys, which was characterized by increased tubular proliferation, lower serum cystatin C and reduced fibrosis after subsequent iri,” remarks Mylonas. “Our work shows that senescent cells are not just passive bystanders or markers of ageing — they actively inhibit kidney repair and regeneration, and this effect can be reversed with drugs.” “we are already investigating the safety and efficacy of aBt-263 as a senolytic in human kidneys that have been rejected for transplantation, using an ex vivo perfusion circuit,” explains Ferenbach. “we will also investigate how ageing inhibits the ability of macrophages and natural killer cells to clear senescent cells,” adds Mylonas. Monica Wang K I D N E Y F I B R O S I S