The inhibition of eIF5A hypusination by GC7, a preconditioning protocol to prevent brain death-induced renal injuries in a preclinical porcine kidney transplantation model

Giraud, Sébastien; Kerforne, Thomas; Zely, Jeremy; Ameteau, Virginie; Couturier, Pierre; Tauc, Michel; Hauet, Thierry

doi:10.1111/ajt.15994

Cited by 25 publications

(38 citation statements)

References 69 publications

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“…We looked in vivo for the metabolic and main physiological effects associated to the overall modifications observed in vitro. Mice were treated daily with GC7 (IP, 3 mg/kg/day; "GC7" group) or with vehicle only (NaCl 0.9% w/v; "ctrl" group) for 72 h, according to the protocol demonstrated to have beneficial effect in rodent and pig models [13][14][15] . No difference was found between control and GC7 treated mice for sodium, potassium and chloride ion contents in plasma and urine ( Supplementary Fig.…”

Section: Impact Of Gc7 Treatment On Mice Physiological Parametersmentioning

confidence: 99%

“…Considering this new concept we have recently shown in mammals that the specific inhibition of eIF5A hypusination by the spermidine analogue N1-guanyl-1,7diamine-heptane (GC7) 12 is able to enhance the ischaemic tolerance both at the cellular and tissue level in a rat kidney model of ischaemia/reperfusion injury 13 . Based on these results, we successfully used GC7 both in a preclinical model of kidney transplantation in pig 14 and in a transient focal cerebral ischaemia (tFCI) model in mice 15 . Indeed, acute systemic administration of GC7 in the donor allowed better functional recovery of the kidney graft in the first case 13,14 and reduced the infarct volume, and motor and cognitive post-stroke deficits in the second 15 .…”

Section: Introductionmentioning

confidence: 99%

“…Based on these results, we successfully used GC7 both in a preclinical model of kidney transplantation in pig 14 and in a transient focal cerebral ischaemia (tFCI) model in mice 15 . Indeed, acute systemic administration of GC7 in the donor allowed better functional recovery of the kidney graft in the first case 13,14 and reduced the infarct volume, and motor and cognitive post-stroke deficits in the second 15 . At the cellular level one of the first observations reported on cultured mouse kidney cells treated with GC7 was a metabolic shift from aerobic oxidative phosphorylation toward anaerobic glycolysis decreasing consequently oxygen consumption.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

et al. 2021

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Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.

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Section: Impact Of Gc7 Treatment On Mice Physiological Parametersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

et al. 2021

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“…Fourthly, several reports in mammals have linked eIF5A with both cellular metabolism and respiration. In these studies, the inhibition of hypusinated eIF5A seems to reduce mitochondrial respiration, while leaving glycolytic ATP synthesis operative, which improves ischaemic conditions and organ transplantation [31][32][33]. Finally, and importantly, a recent report describes the modulation of mitochondrial respiration by eIF5A during macrophage activation [34].…”

Section: Introductionmentioning

confidence: 99%

Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways

Barba‐Aliaga

Villarroel-Vicente

Stanciu

et al. 2020

IJMS

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Translation elongation factor eIF5A binds to ribosomes to promote peptide bonds between problematic amino acids for the reaction like prolines. eIF5A is highly conserved and essential in eukaryotes, which usually contain two similar but differentially expressed paralogue genes. The human eIF5A-1 isoform is abundant and implicated in some cancer types; the eIF5A-2 isoform is absent in most cells but becomes overexpressed in many metastatic cancers. Several reports have connected eIF5A and mitochondria because it co-purifies with the organelle or its inhibition reduces respiration and mitochondrial enzyme levels. However, the mechanisms of eIF5A mitochondrial function, and whether eIF5A expression is regulated by the mitochondrial metabolism, are unknown. We analysed the expression of yeast eIF5A isoforms Tif51A and Tif51B under several metabolic conditions and in mutants. The depletion of Tif51A, but not Tif51B, compromised yeast growth under respiration and reduced oxygen consumption. Tif51A expression followed dual positive regulation: by high glucose through TORC1 signalling, like other translation factors, to promote growth and by low glucose or non-fermentative carbon sources through Snf1 and heme-dependent transcription factor Hap1 to promote respiration. Upon iron depletion, Tif51A was down-regulated and Tif51B up-regulated. Both were Hap1-dependent. Our results demonstrate eIF5A expression regulation by cellular metabolic status.

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“…In this issue of the American Journal of Transplantation , Giraud and Kerforne et al use a preclinical model of porcine kidney transplantation to study the mechanisms of brain death‐induced AKI 1 . The same group previously reported that the eukaryotic initiation factor 5A (eIF5A) hypusination inhibitor N1‐guanyl‐1,7‐diaminoheptane (GC7), a spermidine analog, protects porcine kidneys from ischemic renal injury 2 .…”

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confidence: 99%

Precondition your donor pig for your successful allograft!

Schnieke

Locke

Linkermann

2020

American Journal of Transplantation

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Kidney transplantation has become a lifesaver for patients worldwide. The major organ sources are brain dead donors (BDD). Accumulating evidence suggests that brain death contributes to an impairment of renal function and to nephron loss by acute tubular necrosis (ATN). Together with the surgical procedure, this inevitably results in acute kidney injury (AKI). Devising appropriate models to study brain death-induced AKI and associated delayed graft function (DGF) is technically challenging. In this issue of the American Journal of Transplantation, Giraud and Kerforne et al use a preclinical model of porcine kidney transplantation to study the mechanisms of brain death-induced AKI. 1 The same group previously reported that the eukaryotic initiation factor 5A (eIF5A) hypusination inhibitor N1-guanyl-1,7-diaminoheptane (GC7), a spermidine analog, protects porcine kidneys from ischemic renal injury. 2 They demonstrated that GC7 induced a marked reduction in OXPHOS mitochondrial activity, most likely by selectively targeting components of the respiratory chain complexes 2 and thus reducing the generation of reactive oxygen species (ROS). ROS cause lipid peroxidation and ATN by regulated cell death (RCD) processes. 3 This destructive process is catalyzed by free iron and causes mitochondrial fragmentation and the cellular energetic breakdown, features that are typical of ferroptosis. 4 This differs from apoptosis where the plasma membrane stays intact, and from all other known cell death pathways in that it results in synchronized regulated necrosis (SRN) of nephrons beyond a single cell level, explaining the phenomenon of nephron loss. 5 The necrotic nature of ATN is associated with the release of damage-associated molecular patterns (DAMPs) that drive rejection of transplanted organs. 6 Transplantation of nonnecrotic organs through pharmacological prevention of ATN, for example, by GC7, should therefore result in favorable outcome. Giraud and Kerforne et al induced slow brain death in pigs and then carefully investigated potential hemodynamic changes following application of GC7 (Figure 1). The mean arterial pressure and cardiac output remained unaffected by the compound.

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The inhibition of eIF5A hypusination by GC7, a preconditioning protocol to prevent brain death-induced renal injuries in a preclinical porcine kidney transplantation model

Abstract: Poitou-Charentes (convention number 15/RPC-R-017), Fondation de l'Avenir (Recherche Médicale Appliquée, program ET3-686) and Fondation pour la recherche médicale (FRM) (DPM 20121125559).

Cited by 25 publications

References 69 publications

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

Yeast Translation Elongation Factor eIF5A Expression Is Regulated by Nutrient Availability through Different Signalling Pathways

Precondition your donor pig for your successful allograft!

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