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Kidney Week

Abstract: PO0409

Clearance of Chronic Senescent Tubular Cells by ABT263 After Ischemic AKI Halts the Progression of Established Fibrosis and Restores Tubular Regeneration

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Livingston, Man J., Augusta University Medical College of Georgia, Augusta, Georgia, United States
  • Dong, Zheng, Augusta University Medical College of Georgia, Augusta, Georgia, United States
Background

Emerging studies from aging models demonstrate that increased senescent cell load causes kidney dysfunction and removal of senescent cells by senotherapeutics may rejuvenate aged kidneys for renoprotection. Senescent cells also accumulate in the kidney during maladaptive repair after AKI. However, the pathological role of cellular senescence in post-injury kidney and the therapeutic significance of targeting senescence to treat fibrosis during AKI to CKD transition remain less understood.

Methods

To induce post-ischemic kidney fibrosis, 10 to 12-week-old C57/BL6 mice underwent 30-minute unilateral or 22-minute bilateral renal ischemia followed by reperfusion for 2 weeks. The mice were then treated with either vehicle or ABT263 at 50 mg/kg/day, daily i.p. injection, 5 days/week for 2 weeks. One week after the completion of ABT263 treatment, the morphology and function of the fibrotic kidneys were examined.

Results

Following ischemic AKI, senescent cells accumulated in renal tubules, as indicated by upregulation of p16 and SASP factors, increased tubular staining of SA-β-gal, and induction of γ-H2AX nuclear foci. This injury-induced tubular senescent phenotype was accompanied by persistent interstitial fibrosis. Compared with vehicle treatment, ABT263 significantly eliminated senescent tubular cells and partially suppressed the progression of post-ischemic kidney fibrosis. Along with fibrosis resolution, ABT263 also reduced the infiltration of macrophages in interstitial tissues and attenuated the chronic expression of KIM-1 in injured proximal tubules, therefore creating a pro-regenerative environment for tubular repair. As a result, the number of Ki67-positive tubular cells was promoted and tubular expression of LTL was restored to some extent as well, indicating increased tubular proliferation and redifferentiation. Consistent with the morphological findings, renal function, as assessed by BUN, serum creatinine and eGFR, was also improved in mice treated with ABT-263.

Conclusion

These results support the pathological role of tubular injury-induced accumulation of senescent cells in fibrotic repair after AKI. Targeting these chronic senescent cells by senolytic drugs may represent a therapeutic strategy to reverse maladaptive tubular repair and to halt AKI to CKD progression.

Funding

  • NIDDK Support