O-GlcNAc levels stimulation improves survival at the early phase of septic shock in the young

Abstract

We have shown that increase in O -GlcNAc levels, a post-translational modification, at the early phase of septic shock in adult (84 days old rats) resulted in a 3-fold increase in survival time. Most studies focus only in adults, and the population most affected by septic shock, young children, is rarely studied. Sepsis, with a mortality rate of 29%, is an important but preventable cause of pediatric death worldwide. Considering that basal O- GlcNAc levels are higher in the young, the potential impact of O- GlcNAc stimulation at the early phase of septic shock in the young should be evaluated. Evaluate if O- GlcNAc stimulation could improve sepsis outcomes in young. Endotoxemic shock was induced in 28 days old rats with an i.v. injection of saline (CTRL) or LPS (O111:B4, 20 mg.kg −1 – LPS). 1 hour after LPS rats were randomly assigned to no therapy (LPS), fluidotherapy (saline, 10 mL.kg −1 – LPS + R) ± NButGT (10 mg.kg −1 – NButGT) to increase O- GlcNAc levels. 2 hours later, physiological functions and plasmatic markers were measured and used in adapted Pediatric RISk of Mortality score (PRISM score). The impact of treatment on survival was evaluated on n = 64. LPS induced a shock (mean arterial pressure (MAP): CTRL: 67.2 ± 1.9; LPS: 50.7 ± 2.1; mmHg; P < 0.05), altered biological parameters (lactates: CTRL: 3.92 ± 0.26; LPS: 6.42 ± 0.45; mmol.L −1 ; troponin T: CTRL: 19.7 ± 4.0; LPS: 45.4 ± 11.4; ng.L −1 ; P < 0.05) and PRISM score ( P < 0.05). LPS + R had no beneficial effect while NButGT improves MAP ( P < 0.05), PRISM score ( P < 0.05) and the median survival (NButGT: 36.0; LPS + R: 13.65; hours; P < 0.001) compared to LPS + R treatment. Despite higher O- GlcNAc levels in young population, we demonstrate that O- GlcNAc stimulation is able to improve pups’ response to endotoxemic shock. Our results show that it is the difference in O- GlcNAcylation between the basal levels and the post-stimulation levels that induces protection against septic shock.