Comparative Effects of Phosphoenolpyruvate, a Glycolytic Intermediate, as an Organ Preservation Agent with Glucose and N-Acetylcysteine against Organ Damage during Cold Storage of Mouse Liver and Kidney

Ishitsuka, Yoichi; Fukumoto, Yusuke; Kondo, Yuki; Irikura, Mitsuru; Kadowaki, Daisuke; Narita, Yuki; Hirata, Sumio; Moriuchi, Hiroshi; Maruyama, Toru; Irie, Tetsumi

doi:10.1155/2013/375825

Cited by 8 publications

(5 citation statements)

References 16 publications

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“…Animal models of warm ischemia-induced IRI generated by temporary unilateral or bilateral clamping of renal pedicles or renal arteries have been well-established and widely used in experimental studies (7,44,46). However, to our knowledge, most of the studies on renal cold ischemia were carried out using in vitro or ex vivo models (10,22,28,32,38) in which the graft functions are unable to be assessed in these models, whereas the in vivo models unavoidably include different durations of warm ischemia during procurement and vascular anastomosis. In the present study, we developed a new mouse model of renal IRI that is induced exclusively by cold ischemia, which mimics graft cold storage in preservation solution, and renal function can be evaluated in vivo.…”

Section: Introductionmentioning

confidence: 99%

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

Jin

Wang

Zhang

et al. 2019

American Journal of Physiology-Renal Physiology

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Transplanted kidneys usually experience several episodes of ischemia, including cold ischemia during allograft storage in preservation solution. However, previous studies focusing on cold renal ischemia were only carried out in vitro or ex vivo. In the present study, we developed and characterized an in vivo mouse model of renal ischemia-reperfusion injury (IRI) induced exclusively by cold ischemia. C57BL/6 mice underwent right kidney nephrectomy, and the left kidney was kept cool with circulating cold saline in a kidney cup, while body temperature was maintained at 37°C. We clamped the renal pedicle and flushed out the blood inside the kidney with cold saline via an opening on the renal vein. The severity of renal IRI was examined with different ischemic durations. We found that the mice with <2 h of cold ischemia exhibited no significant changes in renal function or histopathology; animals with 3 or 4 h of cold ischemia developed into mild to moderate acute kidney injury with characteristic features, including the elevation in plasma creatinine concentration and reduction in glomerular filtration rate and tubular necrosis, followed by a subsequent recovery. However, mice with 5 h of cold ischemia died in a few days with severe acute kidney injury. In summary, we generated a mouse model of renal IRI induced exclusively by cold ischemia, which mimics graft cold storage in preservation solution, and renal function can be evaluated in vivo.

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Section: Introductionmentioning

confidence: 99%

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

Jin

Wang

Zhang

et al. 2019

American Journal of Physiology-Renal Physiology

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“…Other downstream effects, such as glucose 6-phosphate or PEP, were found decreased following ischemia. PEP has been shown to exert cytoprotective and anti-oxidative properties that prevent a decrease in ATP content [ 61 , 62 ], which could explain the moderate decrease in ATP under normoxic culture. While an increase in ATP production was observed across all treatments following ischemia, the metabolic profile of treated ischemic cells varied.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells secretome restores bioenergetic and redox homeostasis in human proximal tubule cells after ischemic injury

Faria,

Calcat-i-Cervera,

Skovronova

et al. 2023

Stem Cell Res Ther

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Background Ischemia/reperfusion injury is the leading cause of acute kidney injury (AKI). The current standard of care focuses on supporting kidney function, stating the need for more efficient and targeted therapies to enhance repair. Mesenchymal stromal cells (MSCs) and their secretome, either as conditioned medium (CM) or extracellular vesicles (EVs), have emerged as promising options for regenerative therapy; however, their full potential in treating AKI remains unknown. Methods In this study, we employed an in vitro model of chemically induced ischemia using antimycin A combined with 2-deoxy-d-glucose to induce ischemic injury in proximal tubule epithelial cells. Afterwards we evaluated the effects of MSC secretome, CM or EVs obtained from adipose tissue, bone marrow, and umbilical cord, on ameliorating the detrimental effects of ischemia. To assess the damage and treatment outcomes, we analyzed cell morphology, mitochondrial health parameters (mitochondrial activity, ATP production, mass and membrane potential), and overall cell metabolism by metabolomics. Results Our findings show that ischemic injury caused cytoskeletal changes confirmed by disruption of the F-actin network, energetic imbalance as revealed by a 50% decrease in the oxygen consumption rate, increased oxidative stress, mitochondrial dysfunction, and reduced cell metabolism. Upon treatment with MSC secretome, the morphological derangements were partly restored and ATP production increased by 40–50%, with umbilical cord-derived EVs being most effective. Furthermore, MSC treatment led to phenotype restoration as indicated by an increase in cell bioenergetics, including increased levels of glycolysis intermediates, as well as an accumulation of antioxidant metabolites. Conclusion Our in vitro model effectively replicated the in vivo-like morphological and molecular changes observed during ischemic injury. Additionally, treatment with MSC secretome ameliorated proximal tubule damage, highlighting its potential as a viable therapeutic option for targeting AKI.

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“…PyA, a parent compound of EtPy, and PEP, a precursor of PyA, have been demonstrated to show anti-inflammatory and anti-oxidative potential in previous studies [ 28 , 36 , 37 , 38 ]. Although PEP did not show significant protection against NAPQI-induced cellular injury, PyA tended to attenuate the cytotoxicity induced by NAPQI in the current study.…”

Section: Discussionmentioning

confidence: 99%

Ethyl pyruvate attenuates acetaminophen-induced liver injury and prevents cellular injury induced by N-acetyl-p-benzoquinone imine

Nagatome

Kondo

Kadowaki

et al. 2018

Heliyon

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Acetaminophen, a common analgesic/antipyretic, is a frequent cause of acute liver failure in Western countries. The development of an effective cure against acetaminophen hepatotoxicity is crucial. Ethyl pyruvate, an ethyl ester derivative of pyruvic acid, has been identified as a possible candidate against acetaminophen hepatotoxicity in animal experiments. However, the mode of the hepatoprotective action of ethyl pyruvate remains unclear. We examined the hepatoprotective effect of ethyl pyruvate against hepatocyte injury and oxidative stress in a mouse model of acetaminophen hepatotoxicity. In addition, to examine whether ethyl pyruvate has direct hepatocellular protection against acetaminophen hepatotoxicity to counteract the influence of inflammatory cells, such as macrophages, we examined the effects of ethyl pyruvate on cellular injury induced by N-acetyl-p-benzoquinone imine, a toxic metabolite of acetaminophen, in a human hepatocyte cell line, HepG2 cells. Treatment with ethyl pyruvate significantly prevented increases in serum transaminase levels and hepatic centrilobular necrosis induced with an acetaminophen overdose in mice in a dose-dependent manner. Although hepatic DNA fragmentation induced by acetaminophen was also attenuated with ethyl pyruvate, nitrotyrosine formation was not inhibited. Ehyl pyruvate significantly attenuated mitochondria dehydrogenase inactivity induced by N-acetyl-p-benzoquinone imine in HepG2 cells. The attenuating effect was also observed in a rat hepatocyte cell line. Increases in annexin V and propidium iodide-stained cells induced by N-acetyl-p-benzoquinone imine were prevented with ethyl pyruvate in HepG2 cells. Pyruvic acid, a parent compound of ethyl pyruvate, tended to attenuate these changes. The results indicate that ethyl pyruvate has direct hepatocellular protection against N-acetyl-p-benzoquinone imine induced injury observed in acetaminophen overdose. The in vivo and in vitro results suggest that ethyl pyruvate attenuates acetaminophen-induced liver injury via, at least in part, its cellular protective potential.

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Comparative Effects of Phosphoenolpyruvate, a Glycolytic Intermediate, as an Organ Preservation Agent with Glucose and N-Acetylcysteine against Organ Damage during Cold Storage of Mouse Liver and Kidney

Cited by 8 publications

References 16 publications

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

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

Mesenchymal stromal cells secretome restores bioenergetic and redox homeostasis in human proximal tubule cells after ischemic injury

Ethyl pyruvate attenuates acetaminophen-induced liver injury and prevents cellular injury induced by N-acetyl-p-benzoquinone imine

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