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Abstract
Sepsis capillary leak syndrome (SCLS) is an independent prognostic factor for poor sepsis outcome. We previously demonstrated that α1AMP-activated protein kinase (α1AMPK) prevents sepsis-induced vascular hyperpermeability by mechanisms involving VE-cadherin (VE-Cad) stabilization and activation of p38 mitogen activated protein kinase/heat shock protein of 27 kDa (p38MAPK/HSP27) pathway. Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, has recently been proven to activate AMPK in endothelial cells. Therefore, we hypothesized that canagliflozin could be of therapeutic potential in patients suffering from SCLS. We herein report that canagliflozin, used at clinically relevant concentrations, counteracts lipopolysaccharide-induced vascular hyperpermeability and albumin leakage in wild-type, but not in endothelial-specific α1AMPK-knockout mice. In vitro, canagliflozin was demonstrated to activate α1AMPK/p38MAPK/HSP27 pathway and to preserve VE-Cad’s integrity in human endothelial cells exposed to human septic plasma. In conclusion, our data demonstrate that canagliflozin protects against SCLS via an α1AMPK-dependent pathway, and lead us to consider novel therapeutic perspectives for this drug in SCLS.
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1 Université catholique de Louvain (UCLouvain), Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X); Cliniques Universitaires Saint Luc, Division of Pediatrics, Brussels, Belgium (GRID:grid.48769.34) (ISNI:0000 0004 0461 6320)
2 Université catholique de Louvain (UCLouvain), Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X)
3 Université catholique de Louvain (UCLouvain), Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X); Cliniques Universitaires Saint Luc, Division of Intensive Care, Brussels, Belgium (GRID:grid.48769.34) (ISNI:0000 0004 0461 6320)
4 Université catholique de Louvain (UCLouvain), Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute (LDRI), Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X)
5 Cliniques Universitaires Saint-Luc, Division of Nephrology, Brussels, Belgium (GRID:grid.48769.34) (ISNI:0000 0004 0461 6320); Université catholique de Louvain (UCLouvain), Pôle Nephrologie (NEFR), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X)
6 Paris Cardiovacular Research Center, Inserm U970, Paris, France (GRID:grid.462416.3) (ISNI:0000 0004 0495 1460)
7 Université catholique de Louvain (UCLouvain), Pôle de Recherche Cardiovasculaire (CARD), Institut de Recherche Expérimentale et Clinique (IREC), Brussels, Belgium (GRID:grid.7942.8) (ISNI:0000 0001 2294 713X); Cliniques Universitaires Saint-Luc, Division of Cardiology, Brussels, Belgium (GRID:grid.48769.34) (ISNI:0000 0004 0461 6320)