Korean J Transplant.  2022 Nov;36(Supple 1):S45. 10.4285/ATW2022.F-1589.

Delayed treatment with poly (ADP-Ribose) polymerase inhibitor during healing phase of ischemic acute kidney injury

Affiliations
  • 1Department of Nephrology, Samsung Medical Center, Seoul, Korea
  • 2Department of Pathology, Samsung Medical Center, Seoul, Korea

Abstract

Background
Uncontrolled activation of poly (ADP-Ribose) polymerase (PAPR) after DNA damage through NAD+ depletion ag-gravates tissue injury including postischemic kidney. Although the beneficial effects of PARP inhibition on the early injury phase of renal ischemia-reperfusion injury (IRI) were previously reported, the effects of PARP inhibitors on the healing phase after renal IRI has not been demonstrated. Delayed treatment of JPI-289, a novel PARP inhibitor, was investigated during the healing phase of murine renal IRI and hypoxic HK-2 cell models.
Methods
In murine renal IRI models of unilateral IRI (UIRI) and bilateral IRI (BIRI), male 9-week-old C57BL/6 mice were allocated to the control and the JPI-289 groups and received intraperitoneal injection of saline and JPI-289 50 or 100 mg/kg at 24 or 48 hours after IRI surgery, respectively. Hypoxic HK-2 cells were treated with the JPI-289 and the degree of proliferation was compared.
Results
In BIRI model, renal function initially worsened and then recovered in the JPI-289 treated group compared to the control group. At 12 weeks after UIRI, the JPI-289 100 mg/kg twice treated group showed more prominent renal tubular necrosis and damage, inflammatory cell infiltration, and intrarenal expression of proinflammatory cytokines/chemokines compared to the control group, while those were comparable between the groups at 6 weeks after BIRI or UIRI. The degree of fibrosis was com-parable between the groups. In HK-2 cell hypoxia model, 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, however delayed treatment after 24 hours inhibited proliferation.
Conclusions
Our study suggests possible detrimental effects of delayed treatment with PARP inhibitors on the recovery process of ischemic AKI. Further studies regarding the most optimal timing and dosage of PARP inhibitors to facilitate repair of post-ischemic kidney are required.

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