TY - JOUR
T1 - Proximal Tubule p53 in Cold Storage/Transplantation-Associated Kidney Injury and Renal Graft Dysfunction
AU - Xiang, Xiaohong
AU - Zhu, Jiefu
AU - Zhang, Gang
AU - Ma, Zhengwei
AU - Livingston, Man J.
AU - Dong, Zheng
N1 - Funding Information:
This work was supported partly by Merit Review Award I01 BX000319 from the Department of Veterans Affairs of USA and the grants 5R01DK058831 and 5R01DK087843 from the National Institutes of Health of USA. ZD is a recipient of Senior Research Career Scientist award from the Department of Veterans Affairs of USA.
Publisher Copyright:
Copyright © 2021 Xiang, Zhu, Zhang, Ma, Livingston and Dong.
PY - 2021/10/22
Y1 - 2021/10/22
N2 - Kidney injury associated with cold storage/transplantation is a primary factor for delayed graft function and poor outcome of renal transplants. p53 contributes to both ischemic and nephrotoxic kidney injury, but its involvement in kidney cold storage/transplantation is unclear. Here, we report that p53 in kidney proximal tubules plays a critical role in cold storage/transplantation kidney injury and inhibition of p53 can effectively improve the histology and function of transplanted kidneys. In a mouse kidney cold storage/transplantation model, we detected p53 accumulation in proximal tubules in a cold storage time-dependent manner, which correlated with tubular injury and cell death. Pifithrin-α, a pharmacologic p53 inhibitor, could reduce acute tubular injury, apoptosis and inflammation at 24 h after cold storage/transplantation. Similar effects were shown by the ablation of p53 from proximal tubule cells. Notably, pifithrin-α also ameliorated kidney injury and improved the function of transplanted kidneys in 6 days when it became the sole life-supporting kidney in recipient mice. in vitro, cold storage followed by rewarming induced cell death in cultured proximal tubule cells, which was accompanied by p53 activation and suppressed by pifithrin-α and dominant-negative p53. Together, these results support a pathogenic role of p53 in cold storage/transplantation kidney injury and demonstrate the therapeutic potential of p53 inhibitors.
AB - Kidney injury associated with cold storage/transplantation is a primary factor for delayed graft function and poor outcome of renal transplants. p53 contributes to both ischemic and nephrotoxic kidney injury, but its involvement in kidney cold storage/transplantation is unclear. Here, we report that p53 in kidney proximal tubules plays a critical role in cold storage/transplantation kidney injury and inhibition of p53 can effectively improve the histology and function of transplanted kidneys. In a mouse kidney cold storage/transplantation model, we detected p53 accumulation in proximal tubules in a cold storage time-dependent manner, which correlated with tubular injury and cell death. Pifithrin-α, a pharmacologic p53 inhibitor, could reduce acute tubular injury, apoptosis and inflammation at 24 h after cold storage/transplantation. Similar effects were shown by the ablation of p53 from proximal tubule cells. Notably, pifithrin-α also ameliorated kidney injury and improved the function of transplanted kidneys in 6 days when it became the sole life-supporting kidney in recipient mice. in vitro, cold storage followed by rewarming induced cell death in cultured proximal tubule cells, which was accompanied by p53 activation and suppressed by pifithrin-α and dominant-negative p53. Together, these results support a pathogenic role of p53 in cold storage/transplantation kidney injury and demonstrate the therapeutic potential of p53 inhibitors.
KW - cold storage
KW - kidney injury
KW - kidney transplantation
KW - p53
KW - proximal tubule
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U2 - 10.3389/fmed.2021.746346
DO - 10.3389/fmed.2021.746346
M3 - Article
AN - SCOPUS:85118712157
SN - 2296-858X
VL - 8
JO - Frontiers in Medicine
JF - Frontiers in Medicine
M1 - 746346
ER -