Abstract
Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa (FXa) in an antithrombin-dependent fashion. This newly developed anticoagulant is used in the prevention and treatment of venous thromboembolism. Recently, we showed that fondaparinux reduces inflammation and protects the kidney from ischemia-reperfusion (I/R) injury. However, the relative contributions of the anticoagulant and anti-inflammatory activities of fondaparinux to the observed protection is unknown. To address this, we chemically modified fondaparinux to abolish its affinity for antithrombin and analyzed the effect of this non-anticoagulant (NAC)-pentasaccharide on binding of U937 cells to P-selectin in vitro and on inflammation in a murine model of kidney I/R injury. NAC-pentasaccharide was as effective as fondaparinux at inhibiting the binding of U937 cells to P-selectin. In addition, NAC-pentasaccharide significantly reduced IL-6 and MIP-2 expression and injury in the kidney I/R model. These findings indicate that the anti-inflammatory activity of fondaparinux can be dissociated from its anticoagulant activity and that NAC-pentasaccharide is protective in kidney I/R injury.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Anticoagulants / pharmacology*
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Anticoagulants / therapeutic use
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Blood Coagulation / drug effects
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Cell Adhesion / drug effects
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Chemokine CCL2 / blood
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Chemokine CXCL2
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Chemokines / metabolism
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Creatinine / blood
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Disease Models, Animal
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Factor Xa Inhibitors
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Fondaparinux
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Humans
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Inflammation / blood
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Inflammation / metabolism
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Inflammation / prevention & control*
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Interleukin-6 / blood
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Kidney / blood supply
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Kidney / drug effects*
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Kidney / metabolism
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Kidney / pathology
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Kidney Tubules / drug effects
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Kidney Tubules / pathology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Neutrophil Infiltration / drug effects
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Oligosaccharides / pharmacology*
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Oligosaccharides / therapeutic use
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P-Selectin / metabolism
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Partial Thromboplastin Time
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Polysaccharides / pharmacology*
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Polysaccharides / therapeutic use
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Reperfusion Injury / blood
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Reperfusion Injury / metabolism
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Reperfusion Injury / pathology
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Reperfusion Injury / prevention & control*
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U937 Cells
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Anticoagulants
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Ccl2 protein, mouse
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Chemokine CCL2
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Chemokine CXCL2
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Chemokines
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Cxcl2 protein, mouse
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Factor Xa Inhibitors
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Interleukin-6
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NAC-pentasaccharide
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Oligosaccharides
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P-Selectin
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Polysaccharides
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Creatinine
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Fondaparinux