A mouse model of renal ischemia-reperfusion injury solely induced by cold ischemia

Jin, Wei; Wang, Yingliang; Zhang, Jie; Wang, Lei; Fu, Li-Ying; Byeong, J.; Buggs, Jacentha; Liu, Ruisheng

doi:10.1152/ajprenal.00533.2018

Cited by 22 publications

(17 citation statements)

References 49 publications

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“…In this study, we have provided the first evidence for PKCd regulation of kidney injury in cold-storage transplantation, a model relevant to cold ischemia reperfusion. 16,[49][50][51] We show that kidney injury due to cold storage-associated transplantation was markedly reduced when PKCd was ablated in donor kidneys (Figure 6), indicating an essential role of renal intrinsic PKCd. In line with this observation, we detected PKCd activation in kidney tissues, especially in renal tubules (Figure 2).…”

Section: Discussionmentioning

confidence: 85%

Protein Kinase C-δ Mediates Kidney Tubular Injury in Cold Storage–Associated Kidney Transplantation

Zhu

Zhang

Song

et al. 2020

JASN

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BackgroundKidney injury associated with cold storage is a determinant of delayed graft function and the long-term outcome of transplanted kidneys, but the underlying mechanism remains elusive. We previously reported a role of protein kinase C-δ (PKCδ) in renal tubular injury during cisplatin nephrotoxicity and albumin-associated kidney injury, but whether PKCδ is involved in ischemic or transplantation-associated kidney injury is unknown.MethodsTo investigate PKCδ’s potential role in injury during cold storage–associated transplantation, we incubated rat kidney proximal tubule cells in University of Wisconsin (UW) solution at 4°C for cold storage, returning them to normal culture medium at 37°C for rewarming. We also stored kidneys from donor mice in cold UW solution for various durations, followed by transplantation into syngeneic recipient mice.ResultsWe observed PKCδ activation in both in vitro and in vivo models of cold-storage rewarming or transplantation. In the mouse model, PKCδ was activated and accumulated in mitochondria, where it mediated phosphorylation of a mitochondrial fission protein, dynamin-related protein 1 (Drp1), at serine 616. Drp1 activation resulted in mitochondrial fission or fragmentation, accompanied by mitochondrial damage and tubular cell death. Deficiency of PKCδ in donor kidney ameliorated Drp1 phosphorylation, mitochondrial damage, tubular cell death, and kidney injury during cold storage–associated transplantation. PKCδ deficiency also improved the repair and function of the renal graft as a life-supporting kidney. An inhibitor of PKCδ, δV1-1, protected kidneys against cold storage–associated transplantation injury.ConclusionsThese results indicate that PKCδ is a key mediator of mitochondrial damage and renal tubular injury in cold storage–associated transplantation and may be an effective therapeutic target for improving renal transplant outcomes.

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Section: Discussionmentioning

confidence: 85%

Protein Kinase C-δ Mediates Kidney Tubular Injury in Cold Storage–Associated Kidney Transplantation

Zhu

Zhang

Song

et al. 2020

JASN

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“…However, in the ex vivo setting, hypothermic preservation tended to reduce damage more than subnormothermic temperatures. In a mouse model, experiments with solely cold ischemia showed detrimental kidney damage [52]. Yet, the most suitable preservation temperature depends on many factors and temperature optimization for kidney preservation will require more thorough investigation.…”

Section: Discussionmentioning

confidence: 99%

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

et al. 2019

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Background Hypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation. However, the exact effect of hypothermic kidney preservation on mitochondrial function remains unclear. Methods We evaluated mitochondrial function [i.e. oxygen consumption and production of reactive oxygen species (ROS)] in different models (porcine kidney perfusion, isolated kidney mitochondria, and HEK293 cells) at temperatures ranging 7–37 °C. Results Lowering temperature in perfused kidneys and isolated mitochondria resulted in a rapid decrease in oxygen consumption (65% at 27 °C versus 20% at 7 °C compared to normothermic). Decreased oxygen consumption at lower temperatures was accompanied by a reduction in mitochondrial ROS production, albeit markedly less pronounced and amounting only 50% of normothermic values at 7 °C. Consequently, malondialdehyde (a marker of ROS-induced lipid peroxidation) accumulated in cold stored kidneys. Similarly, low temperature incubation of kidney cells increased lipid peroxidation, which is due to a loss of ROS scavenging in the cold. Conclusions Lowering of temperature highly affects mitochondrial function, resulting in a progressive discrepancy between the lowering of mitochondrial respiration and their production of ROS, explaining the deleterious effects of hypothermia in transplantation procedures. These results highlight the necessity to develop novel strategies to decrease the formation of ROS during hypothermic organ preservation. Electronic supplementary material The online version of this article (10.1186/s12967-019-2013-1) contains supplementary material, which is available to authorized users.

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“…Basic research (6,7) and clinical trial (8) revealed that inhibition of proximal tubular cell death with caspase inhibitors during cold storage improves graft function and histology. Moreover, we (9) and others (10)(11)(12)(13) identified intrinsic mitochondrial pathway of apoptosis in cold storage/transplantation kidney injury. Despite these findings, the cellular and molecular mechanism of cold storage/transplantation kidney injury remains elusive and there is an urgent need for effective renoprotective approaches.…”

Section: Introductionmentioning

confidence: 72%

Proximal Tubule p53 in Cold Storage/Transplantation-Associated Kidney Injury and Renal Graft Dysfunction

et al. 2021

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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.

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A mouse model of renal ischemia-reperfusion injury solely induced by cold ischemia

Cited by 22 publications

References 49 publications

Protein Kinase C-δ Mediates Kidney Tubular Injury in Cold Storage–Associated Kidney Transplantation

Protein Kinase C-δ Mediates Kidney Tubular Injury in Cold Storage–Associated Kidney Transplantation

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

Proximal Tubule p53 in Cold Storage/Transplantation-Associated Kidney Injury and Renal Graft Dysfunction

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