In Vitro/Ex Vivo Models for the Study of Ischemia Reperfusion Injury during Kidney Perfusion

Giraud, Sébastien; Thuillier, Raphaël; Cau, Jérôme; Hauet, Thierry

doi:10.3390/ijms21218156

Cited by 10 publications

(6 citation statements)

References 89 publications

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“…Since the molecular maladaptations we observed, as well as the morphological changes, are in line with findings in acute kidney injury (AKI), and the molecular improvement with addition of NAD has also been described for AKI in vivo ( Arykbaeva et al, 2021 ) ( Faivre et al, 2021 ; Morevati et al, 2021 ) ( Morevati et al, 2021 ), KSI could additionally be a model well suited to study drug treatment for the acute phases of ischemic AKI. Other ex-vivo techniques for the study of ischemia-reperfusion (e.g., cell culture microflow chamber) take comparable approaches ( Giraud et al, 2020 ). Compared to these, KSI has the advantage of intact anatomy and the disadvantage of a shorter time of observation.…”

Section: Discussionmentioning

confidence: 99%

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A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

et al. 2022

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Kidney transplantation is the only definitive therapy for end-stage kidney disease. The shortage of organs for transplantation is the main limitation of this life-saving treatment. Normothermic machine perfusion (NMP) is a novel preservation technique with the potential to increase the number of transplantable kidneys through reducing delayed graft function and organ evaluation under physiological conditions. To date, the cellular effects and possible pharmacological interventions during machine perfusion are incompletely understood. A major limitation is the technically complex, time-consuming, and small-scale replication of NMP in rodent models. To overcome this, we developed a 3D-printed, high throughput ex-vivo mouse kidney slice incubator (KSI) mimicking mouse kidney NMP by working under closely resembling conditions. KSI significantly reduced the time per experiment and increased the sample throughput (theoretical: 54 incubations with n = 500/day). The model recapitulated the cellular responses during NMP, namely increased endoplasmic reticulum stress (ER stress). Using KSI, five pharmacological interventions against ER stress taken from the literature were tested. While four were ineffective and excluded, one, β-Nicotinamide-adenine-dinucleotide (NADH), ameliorated ER stress significantly during KSI. The test of NADH in mouse kidney NMP replicated the positive effects against ER stress. This suggests that testing the addition of NADH during clinical kidney NMP might be warranted.

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Section: Discussionmentioning

confidence: 99%

“…One solution may be increased use of marginal organs, organs in less than an optimal condition that would normally not be transplanted ( Noble et al, 2019 ). However, these organs are more prone to ischemic injury, delayed graft function, and associated long-term complications ( Giraud et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

et al. 2022

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“…Specific programs, both in terms of endothelial cell origin and larger organ experiments, will need to be conducted to consolidate the concepts uncovered herein. Our work opens the possibility to further investigation in models proposing a higher level of sophistication [ 55 ]. Such a model would permit for instance to mimic perfusion, such as with microfluidic chambers, as the use of machine perfusion is increasing, particularly for marginal donors, and provide answers to the rising interest in designing novel therapeutics compatible with this mode of preservation [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

High Throughput Proteomic Exploration of Hypothermic Preservation Reveals Active Processes within the Cell Associated with Cold Ischemia Kinetic

Pasini-Chabot

Vincent

Pape

et al. 2021

IJMS

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The demand for organs to be transplanted increases pressure on procurement centers, to the detriment of organ quality, increasing complications. New preservation protocols are urgently needed, requiring an in-depth understanding of ischemia-reperfusion mechanisms. We performed a proteomic analysis using LC-MS/MS-TOF data analyzed through R software and Cytoscape's ClueGO application, comparing the proteome of kidney endothelial cells, key cell type, subjected to 3, 6, 12, 19, and 24 h of cold ischemia and 6 h reperfusion. Critical pathways such as energy metabolism, cytoskeleton structure/transport system, and gene transcription/translation were modulated. Important time windows were revealed: a—during the first 3 h, central proteins were upregulated within these pathways; b—the majority of these upregulations were maintained until 12 h cold ischemia time (CIT); c—after that time, the overall decrease in protein expression was observed; d—at reperfusion, proteins expressed in response to cold ischemia were all downregulated. This shows that cold ischemia is not a simple slowing down of metabolism, as deep changes take place within the proteome on major pathways. Time-sensitive expression of key protein reveals possible quality biomarkers as well as potential targets for new strategies to maintain or optimize organ quality.

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“…With regard to biomaterial evaluation, ex vivo tests are performed to study the physical, chemical, mechanical, and other properties of biomaterials that have interacted with tissue after being implanted for a time or during the interaction. These models also have a new interest for transplantation and organ preservation, taking into account the development of machine preservation and normothermic perfusion, particularly for lung, kidney, and liver [ 54 , 55 ]. In addition, new developments of ex vivo can be expected with cellular bioengineering methods (organotypic cultures based on 3D cultures of primary cells, organoids and “organ-on chips” technology, and genetically modified animals).…”

Section: Models Of Oxidative Stressmentioning

confidence: 99%

Oxidative Stress Evaluation in Ischemia Reperfusion Models: Characteristics, Limits and Perspectives

Chazelas

Steichen

Favreau

et al. 2021

IJMS

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Ischemia reperfusion injury is a complex process consisting of a seemingly chaotic but actually organized and compartmentalized shutdown of cell function, of which oxidative stress is a key component. Studying oxidative stress, which results in an imbalance between reactive oxygen species (ROS) production and antioxidant defense activity, is a multi-faceted issue, particularly considering the double function of ROS, assuming roles as physiological intracellular signals and as mediators of cellular component damage. Herein, we propose a comprehensive overview of the tools available to explore oxidative stress, particularly in the study of ischemia reperfusion. Applying chemistry as well as biology, we present the different models currently developed to study oxidative stress, spanning the vitro and the silico, discussing the advantages and the drawbacks of each set-up, including the issues relating to the use of in vitro hypoxia as a surrogate for ischemia. Having identified the limitations of historical models, we shall study new paradigms, including the use of stem cell-derived organoids, as a bridge between the in vitro and the in vivo comprising 3D intercellular interactions in vivo and versatile pathway investigations in vitro. We shall conclude this review by distancing ourselves from “wet” biology and reviewing the in silico, computer-based, mathematical modeling, and numerical simulation options: (a) molecular modeling with quantum chemistry and molecular dynamic algorithms, which facilitates the study of molecule-to-molecule interactions, and the integration of a compound in a dynamic environment (the plasma membrane...); (b) integrative systemic models, which can include many facets of complex mechanisms such as oxidative stress or ischemia reperfusion and help to formulate integrated predictions and to enhance understanding of dynamic interaction between pathways.

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In Vitro/Ex Vivo Models for the Study of Ischemia Reperfusion Injury during Kidney Perfusion

Cited by 10 publications

References 89 publications

A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

A high-throughput drug discovery pipeline to optimize kidney normothermic machine perfusion

High Throughput Proteomic Exploration of Hypothermic Preservation Reveals Active Processes within the Cell Associated with Cold Ischemia Kinetic

Oxidative Stress Evaluation in Ischemia Reperfusion Models: Characteristics, Limits and Perspectives

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