Preventive GC7 reduces brain death-induce renal injuries in a preclinical porcine model

S. Giraud (1, 2, 3) , T. Kerforne (1, 2, 4) , Philippine Couturier (5, 2, 3) , S. Inal (2, 3, 6) , P. Hannaert (7, 1, 2) , M. Tauc (8, 7) , T. Hauet (5, 9, 2, 3, 6, 1)

1 Université de Poitiers - Faculté de Médecine et de Pharmacie
2 IRTOMIT [Poitiers] - Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques [U 1082]
3 Service de Biochimie
4 Département d’Anesthésie-Réanimation
5 GenESI - Génétique, Expérimentation et Système Innovants
6 FHU SUPORT - Fédération Hospitalo-universitaire SUrvival oPtimization in ORgan Transplantation
7 CNRS - Centre National de la Recherche Scientifique
8 LP2M - Laboratoire de PhysioMédecine Moléculaire
9 INRA - Institut National de la Recherche Agronomique

N1-guanyl-1,7-diaminoheptane (GC7), an inhibitor of eIF5A, exhibits anti-inflammatory features and promotes anoxic/ischemic tolerance. Thus, GC7 pretreatment could be useful in order to protect organs submitted to ischemia before transplantation in heart-beating donors. Methods: Using a pig brain death donation preclinical model, we carried out the in vivo evaluation of GC7 pre-treatment (3 mg/kg iv bolus), after brain death, at the beginning of the 4 h-reanimation, after which one kidney was collected, cold-stored (18-h in UW), and allo-transplantated in a doublenephrectomized recipient. Groups were defined as follows (n = 6 per group): healthy (Control), untreated Brain death (BD) and GC7-treated BD (GC7). Results: R1. At the end of 4 h-reanimation, GC7 decreased (80–100%, p < 0.05) BD-increased markers: (i) eIF5A hypusination, (ii) tissue levels of reactive oxygen species markers (CellRox staining and Aconitase), (iii) tissue levels of nitrotyrosine, and (iv) the mitochondrial-dependent apoptosis pathway (Bax/Bcl-2 proapoptotic ratio, Caspase-9). In addition, GC7 increased (2 to 6- fold, p < 0.05) the expression of anti-oxidant proteins (SOD2 and HO-1, as well as PGC-1a, Nrf2, and total & p-Sirtuin1 & 3). R2. At the end of cold storage, GC7 treatment normalized BD-dependent decrease of SOD2 and HO-1 proteins expression (p < 0.05). In addition, GC7 significantly restored the BDdependent increase of the Bax/Bcl-2 (proapoptotic) ratio (p < 0.05). Conclusion: After the reanimation phase, preventively given GC7 proved protective for kidneys against brain death-induced injuries; during the cold storage phase, GC7 appeared to preserve antioxidant defences and to protect mitochondria. Early and long-term, post-transplantation propagation of observed protective effects are currently evaluated.

Domaines: Sciences du Vivant [q-bio]

S. Giraud, T. Kerforne, Philippine Couturier, S. Inal, P. Hannaert, et al.. Preventive GC7 reduces brain death-induce renal injuries in a preclinical porcine model. 16. Annual Congress of the French Speaking Society of Transplantation, Dec 2016, Liège, Belgium, Belgium. 29 p., ⟨10.1111/tri.12885⟩. ⟨hal-01603786⟩