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

ABSTRACT 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.