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Kidney Week

Abstract: FR-PO132

Effects of Delayed Treatment With Poly (ADP-Ribose) Polymerase Inhibitor After Ischemia-Reperfusion on Healing Phase of Renal Injury

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Jeon, Junseok, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Jeon, Hojin, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Yoon, Sung Bin, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Lee, Kyungho, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Jang, Hye Ryoun, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Lee, Jung eun, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Kim, Yoon-Goo, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
  • Huh, Wooseong, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (the Republic of)
Background

Excessive activation of poly (ADP-Ribose) polymerase (PAPR) after DNA damage aggravates tissue injury, including postischemic kidney, through NAD+ depletion. The beneficial effects of PARP inhibition on the early injury phase of renal ischemia-reperfusion injury (IRI) was demonstrated in several studies. However, the role of PARP inhibitions on the healing phase after renal IRI has not yet been determined. The effects of JPI-289, a novel PARP inhibitor, on the healing phase of ischemic AKI were investigated in murine renal IRI and hypoxic HK-2 cell models.

Methods

Male 9-week-old C57BL/6 mice were used for renal IRI surgery. Saline (control) or JPI-289 was injected into the peritoneum. JPI-289 100 mg/kg was administered twice at 24 and 48 hours after unilateral IRI (UIRI), and 50 or 100 mg/kg was administered once at 24 hours after UIRI or bilateral IRI (BIRI). HK-2 cells were treated with the JPI-289 after hypoxic insult.

Results

Renal function initially worsened and then recovered in the JPI-289 treated group compared to the control group after BIRI, but was comparable between groups after UIRI. Renal tubular necrosis and damage, inflammatory cell infiltration, and intrarenal expression of proinflammatory cytokines/chemokines were more prominent in the JPI-289 100 mg/kg twice treated group at 12 weeks after UIRI compared to the control group, although those were comparable between groups at 6 weeks after BIRI or UIRI. The extent of fibrosis was similar between the groups. JPI-289 treatment of 0.5 and 0.75 mg/mL at 3 or 6 hours after hypoxia facilitated the proliferation of hypoxic HK-2 cells, whereas further treatment after 24 hours suppressed proliferation even with lower dosages.

Conclusion

Our results suggest that late treatment of PARP inhibitors after renal IRI did not have a beneficial effect on the recovery of ischemic AKI, but rather could have a negative effect on healing.

Funding

  • Government Support – Non-U.S.