O-GlcNAcylation Stimulation Modulates Na+/K+ ATPase and Improves Outcomes in Hemorrhagic Shock

Hemorrhagic shock (HS), caused by blood loss leading to inadequate organ perfusion, remains a major cause of death worldwide, with 1.9 million fatalities annually. It triggers severe disturbances in cardiovascular, neurohormonal, and metabolic homeostasis with ionic imbalance notably due to Na⁺/K⁺-ATPase dysfunction. O-GlcNAcylation, a post-translational modification essential for cellular protection under stress, has emerged as a promising therapeutic target in ischemia-reperfusion and septic shock. This study aimed to determine the effects of stimulating O-GlcNAcylation during HS and to clarify the related molecular mechanisms. Adult male rats were subjected to controlled HS and received either NButGT (2 injections of 10 mg/kg) to enhance O-GlcNAcylation or saline. Hemodynamic parameters and plasmatic markers of organ injury were assessed after 24 h. O-GlcNAcylation levels, protein expression, and Na⁺/K⁺-ATPase O-GlcNAcylation were analyzed via Western blot and immunofluorescence, while Na⁺/K⁺-ATPase activity was measured by colorimetry. NButGT increased cardiac and renal O-GlcNAcylation levels, improved hemodynamic and reduced organ damage. HS disrupts electrolyte homeostasis with decreased bicarbonate and sodium levels and elevated potassium concentration. NButGT administration restored ionic balance and renal Na⁺/K⁺-ATPase expression. Treatment with NButGT elevated Na⁺/K⁺-ATPase activity. These results demonstrate that acute O-GlcNAcylation stimulation supports physiological recovery in HS by promoting ionic homeostasis and Na⁺/K⁺-ATPase function.