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

• DOI: 10.1111/ajt.15994
• Publication Date: 2020-05-13T10:20:51Z
• Authors: Sebastien Giraud; Thomas Kerforne; Jeremy Zely; Virginie Ameteau; Pierre Couturier; Michel Tauc; Thierry Hauet
• Keywords: 0301 basic medicine; Brain Death; Adenosine; translational research/science; kidney (allograft) function / dysfunction; Swine; [SDV]Life Sciences [q-bio]; Allopurinol; Organ Preservation Solutions; ischemia-reperfusion injury (IRI); RNA-Binding Proteins; kidney transplantation/nephrology; Kidney; Glutathione; Kidney Transplantation; 3. Good health; 03 medical and health sciences; Raffinose; Peptide Initiation Factors; Reperfusion Injury; Animals; Insulin

The eIF5A hypusination inhibitor GC7 (N1-guanyl-1,7-diaminoheptane) was shown to protect from ischemic injuries. We hypothesized that GC7 could be useful for preconditioning kidneys from donors before transplantation. Using a preclinical porcine brain death (BD) donation model, we carried out in vivo evaluation of GC7 pretreatment (3 mg/kg iv, 5 minutes after BD) at the beginning of the 4h-donor management, after which kidneys were collected and cold-stored (18h in University of Wisconsin solution) and 1 was allotransplanted. Groups were defined as following (n = 6 per group): healthy (CTL), untreated BD (Vehicle), and GC7-treated BD (Vehicle + GC7). At the end of 4h-management, GC7 treatment decreased BD-induced markers, as radical oxygen species markers. In addition, GC7 increased expression of mitochondrial protective peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC1α) and antioxidant proteins (superoxyde-dismutase-2, heme oxygenase-1, nuclear factor [erythroid-derived 2]-like 2 [NRF2], and sirtuins). At the end of cold storage, GC7 treatment induced an increase of NRF2 and PGC1α mRNA and a better mitochondrial integrity/homeostasis with a decrease of dynamin- related protein-1 activation and increase of mitofusin-2. Moreover, GC7 treatment significantly improved kidney outcome during 90 days follow-up after transplantation (fewer creatininemia and fibrosis). Overall, GC7 treatment was shown to be protective for kidneys against BD-induced injuries during donor management and subsequently appeared to preserve antioxidant defenses and mitochondria homeostasis; these protective effects being accompanied by a better transplantation outcome.