Effects of Ischemia-Reperfusion on Tubular Cell Membrane Transporters and Consequences in Kidney Transplantation

Faucher, Quentin; Alarcan, Hugo; Marquet, Pierre; Guellec, Chantal Barin‐Le

doi:10.3390/jcm9082610

Cited by 22 publications

(27 citation statements)

References 187 publications

(243 reference statements)

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“…Renal tubular membrane transporters (mainly of the SoLute Carrier (SLC) and ATP Binding-Cassette (ABC) families) play a major role in cell and tissue homeostasis owing to the bidirectional, transcellular exchanges they are involved in. Alteration of their activity, previously demonstrated (mainly for SLC) during ischemia or ischemia/reperfusion 13,14 , could be responsible for some metabolic variations observed during organ perfusion, but also have deleterious consequences for the graft outcomes 15 . Concerning the predictive value of the perfusion fluid metabolomic content, controversial results have been found and a recent review suggests that further studies are needed 16 .…”

Section: Introductionmentioning

confidence: 95%

Perfusate metabolomics content and tubular transporters expression during kidney graft preservation by hypothermic machine perfusion

Faucher

Alarcan

Sauvage

et al. 2021

Preprint

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Background: Ischemia-related injury during the pre-implantation period impacts kidney graft outcome. Evaluating these lesions by a non-invasive approach before transplantation could help to understand the mechanisms of graft injury and identify potential biomarkers predictive of graft outcomes. This study aims to determine metabolomic content of graft perfusion fluids and its dependence on preservation time and to explore whether tubular transporters are possibly involved in the metabolomics variations observed. Methods: Kidneys were stored on hypothermic perfusion machines. We evaluated the metabolomic profiles of perfusion fluids (n=35) using Liquid Chromatography coupled with tandem Mass Spectrometry and studied the transcriptional expression of tubular transporters on pre-implantation biopsies (n=26). We used univariate and multivariate analyses to assess the impact of perfusion time on these parameters and their relationship with graft outcome. Results: Seventy-two metabolites were found in preservation fluids at the end of perfusion, of which 40% were already present in the native conservation solution. We observed an increase of 23 metabolites with longer perfusion time and a decrease for 8. The predictive model for time-dependent variation of metabolomics content showed good performance (R2= 76%, Q2= 54%, accuracy= 41%, permutations test significant). Perfusion time had no effect on the mRNA expression of transporters. We found no correlation between metabolomics and transporters expression. Neither the metabolomics profile nor the transporters expression were predictive of graft outcome. Conclusion: Our results open the way for further studies, focusing on both intra- and extra-tissue metabolome, to investigate whether transporter alterations can explain the variations observed in pre-implantation period.

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Section: Introductionmentioning

confidence: 95%

Perfusate metabolomics content and tubular transporters expression during kidney graft preservation by hypothermic machine perfusion

Faucher

Alarcan

Sauvage

et al. 2021

Preprint

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Section: Oxidative Stress and Mitochondrial Dysfunction In I/r Injurymentioning

confidence: 99%

“…The principal consequences of I/R injury are associated to profound alterations of renal epithelial cells that include brush border loss, cytoskeletal changes and rapid loss of surface markers and peculiar transport properties that enhance death mechanisms ( 93 ). All these functional and structural changes induce epithelial cell desquamation and the appearance of cellular debris aggregates in the tubular lumen ( 93 ). Recently, emerging evidences underline that oxidative stress may promote epigenetic modifications of DNA inducing the acquirement of a senescent phenotype that could be the priming of chronic renal damage ( 68 , 94 ).…”

Section: Oxidative Stress and Mitochondrial Dysfunction In I/r Injurymentioning

confidence: 99%

Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials

et al. 2021

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Donor organ shortage still remains a serious obstacle for the access of wait-list patients to kidney transplantation, the best treatment for End-Stage Kidney Disease (ESKD). To expand the number of transplants, the use of lower quality organs from older ECD or DCD donors has become an established routine but at the price of increased incidence of Primary Non-Function, Delay Graft Function and lower-long term graft survival. In the last years, several improvements have been made in the field of renal transplantation from surgical procedure to preservation strategies. To improve renal outcomes, research has focused on development of innovative and dynamic preservation techniques, in order to assess graft function and promote regeneration by pharmacological intervention before transplantation. This review provides an overview of the current knowledge of these new preservation strategies by machine perfusions and pharmacological interventions at different timing possibilities: in the organ donor, ex-vivo during perfusion machine reconditioning or after implementation in the recipient. We will report therapies as anti-oxidant and anti-inflammatory agents, senolytics agents, complement inhibitors, HDL, siRNA and H2S supplementation. Renal delivery of pharmacologic agents during preservation state provides a window of opportunity to treat the organ in an isolated manner and a crucial route of administration. Even if few studies have been reported of transplantation after ex-vivo drugs administration, targeting the biological pathway associated to kidney failure (i.e. oxidative stress, complement system, fibrosis) might be a promising therapeutic strategy to improve the quality of various donor organs and expand organ availability.

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“…Although most research has focused on preventing T-cell responses that lead to acute rejection in a more specific and less toxic way, none of these problems have been completely overcome. Transplantation is a state of ischemia-reperfusion, and the main factors affecting organ function after transplantation are nutrient deprivation and hypoxia, with reperfusion aggravating organ damage initially caused by ischemia ( 197 ). Oxidative stress, apoptosis, and a non-specific innate immune response that subsequently activates the specific immune system are the leading causes of deteriorated early graft function ( 198 ).…”

Section: Kidney Transplantationmentioning

confidence: 99%

Immunomodulatory Effects of Heme Oxygenase-1 in Kidney Disease

Han

et al. 2021

Front. Med.

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Kidney disease is a general term for heterogeneous damage that affects the function and the structure of the kidneys. The rising incidence of kidney diseases represents a considerable burden on the healthcare system, so the development of new drugs and the identification of novel therapeutic targets are urgently needed. The pathophysiology of kidney diseases is complex and involves multiple processes, including inflammation, autophagy, cell-cycle progression, and oxidative stress. Heme oxygenase-1 (HO-1), an enzyme involved in the process of heme degradation, has attracted widespread attention in recent years due to its cytoprotective properties. As an enzyme with known anti-oxidative functions, HO-1 plays an indispensable role in the regulation of oxidative stress and is involved in the pathogenesis of several kidney diseases. Moreover, current studies have revealed that HO-1 can affect cell proliferation, cell maturation, and other metabolic processes, thereby altering the function of immune cells. Many strategies, such as the administration of HO-1-overexpressing macrophages, use of phytochemicals, and carbon monoxide-based therapies, have been developed to target HO-1 in a variety of nephropathological animal models, indicating that HO-1 is a promising protein for the treatment of kidney diseases. Here, we briefly review the effects of HO-1 induction on specific immune cell populations with the aim of exploring the potential therapeutic roles of HO-1 and designing HO-1-based therapeutic strategies for the treatment of kidney diseases.

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Effects of Ischemia-Reperfusion on Tubular Cell Membrane Transporters and Consequences in Kidney Transplantation

Cited by 22 publications

References 187 publications

Perfusate metabolomics content and tubular transporters expression during kidney graft preservation by hypothermic machine perfusion

Perfusate metabolomics content and tubular transporters expression during kidney graft preservation by hypothermic machine perfusion

Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials

Immunomodulatory Effects of Heme Oxygenase-1 in Kidney Disease

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