Canagliflozin protects the vascular barrier during sepsis by AMPK dependant mechanisms - 25/09/20
Résumé |
Introduction |
Vascular hyperpermeability is a major aspect of sepsis pathophysiology. We previously demonstrated that AMPK protects against sepsis induced vascular hyperpermeability by mechanisms involving interendothelial junctions (IEJs) regulation. The SGLT2 inhibitor Canagliflozin, prescribed in diabetes and known for its cardiovascular protective properties, has recently been shown to activate AMPK in different cell types.
Objectives |
Here, we show that Canagliflozin might be considered as a new therapeutic approach against sepsis induced vascular hyperpermeability. We also decipher molecular mechanisms underlying this protective effect.
Methods |
In vivo experiments were performed on endothelial-specific α1AMPK knockout (e-AMPK KO) mice. Canagliflozin administration was achieved by oral gavage (100mg/kg) and validated by plasmatic dosages. LPS was administered by intraperitoneal injection (10mg/kg). Myocardial edema was assessed by Evans Blue Dye extravasation measurement. In vitro experiments were performed in Human Dermal Blood Endothelial Cells (HDBEC). α1AMPK was invalidated with a specific siRNA or activated by Canagliflozin (10μM).
Results |
We show that Canagliflozin activates AMPK in HDBEC at physiological concentrations. Canagliflozin administration strongly protects against LPS induced vascular leakage in WT but not in e-AMPK KO mice. Accordingly, albuminemia is preserved by Canagliflozin treatment in septic WT mice. More interestingly, Canagliflozin treatment increases survival in response to sepsis injury. In vitro, AMPK activation by Canagliflozin preserves the integrity of IEJs (Cx43, VeCad, ZO1).
Conclusion |
Our work demonstrates the protective effects of Canagliflozin on sepsis induced vascular hyperpermeability and mortality, and highlights key molecular mechanisms involved in this protection. This should open the field to consider Canagliflozin as a new therapeutic support of sepsis induced vascular hyperpermeability.
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Vol 12 - N° 2-4
P. 206 - octobre 2020 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.