Preventive GC7 reduces brain death-induce renal injuries in a preclinical porcine model
2016
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.
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