Research ArticleKidney Disease

Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair

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Science Translational Medicine  19 May 2021:
Vol. 13, Issue 594, eabb0203
DOI: 10.1126/scitranslmed.abb0203

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Removing senescent cells restarts renal regeneration

Senescent cells are metabolically active, permanently growth-arrested cells associated with aging and age-related illnesses. Mylonas et al. studied whether senescent cells contribute to the reduced regeneration seen in aged and injured kidneys and whether depletion of these cells using the compound ABT-263 improved kidney function and repair after injury. They found that ABT-263 targeted senescent proximal tubular epithelial cells, and in aged mouse models of acute kidney injury, treatment resulted in improved functional recovery and reduced fibrosis. Experiments using irradiation to induce cellular senescence in young mice showed similar results after acute kidney injury. Senescent cells therefore represent a potential target to protect the kidneys.

Abstract

The ability of the kidney to regenerate successfully after injury is lost with advancing age, chronic kidney disease, and after irradiation. The factors responsible for this reduced regenerative capacity remain incompletely understood, with increasing interest in a potential role for cellular senescence in determining outcomes after injury. Here, we demonstrated correlations between senescent cell load and functional loss in human aging and chronic kidney diseases including radiation nephropathy. We dissected the causative role of senescence in the augmented fibrosis occurring after injury in aged and irradiated murine kidneys. In vitro studies on human proximal tubular epithelial cells and in vivo mouse studies demonstrated that senescent renal epithelial cells produced multiple components of the senescence-associated secretory phenotype including transforming growth factor β1, induced fibrosis, and inhibited tubular proliferative capacity after injury. Treatment of aged and irradiated mice with the B cell lymphoma 2/w/xL inhibitor ABT-263 reduced senescent cell numbers and restored a regenerative phenotype in the kidneys with increased tubular proliferation, improved function, and reduced fibrosis after subsequent ischemia-reperfusion injury. Senescent cells are key determinants of renal regenerative capacity in mice and represent emerging treatment targets to protect aging and vulnerable kidneys in man.

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