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Abstract: FR-PO164

AKI-Induced Senescence as a Key Player in CKD Progression: Insights from an Aristolochic Acid Mouse Model

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Gao, Peng, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
  • Cenatus, Schrodinger Carmax, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada
  • Henley, Nathalie, Hopital Maisonneuve-Rosemont Centre de Recherche Axe de Nephrologie, Montreal, Quebec, Canada
  • Barrera-Chimal, Jonatan, Hopital Maisonneuve-Rosemont Centre de Recherche Axe de Nephrologie, Montreal, Quebec, Canada
  • Gerarduzzi, Casimiro, Universite de Montreal Faculte de Medecine, Montreal, Quebec, Canada

Senescence is a persistent cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP). The role of tubular senescence in driving chronic kidney disease (CKD) following acute kidney injury (AKI) remains controversial due to the multiple animal models used and different timepoints of senescent cell depletion. To accurately represent a direct injury induction of tubular senescence, we utilized a mouse model of Aristolochic acid (AA), a nephrotoxicant known in the clinical setting to promote DNA damage specifically in tubular epithelial cells (TECs). Our model of persistent injury following AA-induction of AKI leads to tubular senescence and allows to study diverse timepoints of CKD progression.


An AKI to CKD model was created by a single intraperitoneal injection of 5 mg/kg of AA into male C57BL/6 mice. In vitro studies utilized 1-10ug/ml AA, and HK-2 (human proximal tubule cell line), mTECs (primary mouse TECs), and NRK-49F (kidney fibroblast cell line). Senolytics (ABT-263) were used to eradicate senescent cells, while senomorphics (Metformin) inhibited SASP.


In vivo: Compared to the control, AA-induced tubular senescence as early as 7 days post-injury, as shown by increased p53, p21, p16, γH2AX expression, and β-Gal activity in tubules. AA-treated mice displayed CKD signs of tubular damage and tubulointerstitial fibrosis. Timing of senolytic treatment affected therapeutic outcomes, with early clearance of senescent cells post AA injection protecting against fibrosis. Clearance of SASP factors using Metformin from day 3 post AA injection mitigated renal fibrosis and senescent burden.
In vitro: AA-induced senescence in HK-2 and mTECs. Senescent HK-2 cell-derived conditioned medium promoted epithelial-to-mesenchymal transition in HK-2 cells and fibroblast-to-myofibroblast transition in NRK-49F cells, which was reversed by Metformin treatment.


Using a model of specific tubular DNA damage, our data reveal that: i) TEC senescence is a key link in the AKI to CKD transition; ii) Precise timing of senescent cell removal by senolytic treatment is critical to achieving therapeutic benefits; iii) Therapeutic inhibition of SASP by senomorphics reduces renal fibrosis and senescence, offering a potential alternative to senolytics.


  • Government Support – Non-U.S.