Abstract: PO2046
p53 Is Activated in Cold Storage/Transplantation to Mediate Tubular Injury and Renal Graft Dysfunction
Session Information
- Transplantation: Evaluating Kidney Graft Injury - Pathways and Biomarkers
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Transplantation
- 1901 Transplantation: Basic
Authors
- Xiang, Xiaohong, Second Xiangya Hospital, Changsha, Hunan, China
- Dong, Zheng, Second Xiangya Hospital, Changsha, Hunan, China
Background
Kidney injury associated with cold storage/transplantation is a leading cause of delayed graft function and poor outcome of renal transplants. p53 has been implicated in both ischemic and nephrotoxic kidney injury, but its involvement in kidney cold storage/transplantation is not clear. This study aimed to investigate the role of p53 in cold storage/transplantation kidney injury and test the therapeutic effects of p53 inhibition.
Methods
Donor kidneys from C57BL/6 mice were preserved in ice-cold University of Wisconsin (UW) solution for 0.5, 2, 6 or 8.5h and transplanted into syngeneic recipients for 24h. Tubular injury, cell death and p53 activation were observed and their correlations were assessed. The acute response of kidneys from pifithrin-α and DMSO (the vehicle solution) treated mice was examined and compared, as well as response of kidneys from p53 conditional knock out (KO) mice and their wild type (WT) littermates. To explore the therapeutic potential of p53 inhibition, pifithrin-α was also administered to test its effect on graft injury and function on day 6, when the graft became the sole life-supporting kidney after native kidney removal at day 5. Rat kidney proximal tubule cells (RPTCs) were incubated in UW solution at 4°C for cold storage, followed by full medium replacement at 37°C for rewarming. Pifithrin-α was added to UW solution or dominant negative p53 was transfected into RPTCs, for the purpose of evaluating their effect on RPTCs death in cold storage/rewarming.
Results
p53 was activated in kidney tubule cells during cold storage transplantation, which correlated with tubular injury and cell death. Pifithrin-α significantly reduced acute tubular injury, cell death and inflammation during cold storage/transplantation. Similar effects were shown by ablation of p53 specifically from kidney proximal tubule cells. Notably, pifithrin-α also ameliorated kidney injury and improved the function of transplanted kidneys as the life-supporting graft. In RPTCs, cold storage followed by rewarming induced cell death and p53 activation. Both pifithrin-α and dominant-negative p53 could attenuate RPTC cell death during cold storage/rewarming.
Conclusion
p53 plays a critical role in kidney injury and dysfunction during cold storage/transplantation. p53 inhibitors may provide therapeutic benefits for donor kidney preservation and transplantation.
Funding
- NIDDK Support