A non-anticoagulant synthetic pentasaccharide reduces inflammation in a murine model of kidney ischemia-reperfusion injury.
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.
Frank
Rolf Dario
RD
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Holscher
Todd
T
Schabbauer
Gernot
G
Tencati
Michael
M
Pawlinski
Rafal
R
Weitz
Jeffrey I
JI
Mackman
Nigel
N
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D018932:Chemokine CCL2 / Q000097:blood; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D065427:Factor Xa Inhibitors; D000077425:Fondaparinux; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D009844:Oligosaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D019007:P-Selectin / Q000378:metabolism; D010314:Partial Thromboplastin Time; D011134:Polysaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020298:U937 Cells
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D065427:Factor Xa Inhibitors; D015850:Interleukin-6; C517148:NAC-pentasaccharide; D009844:Oligosaccharides; D019007:P-Selectin; D011134:Polysaccharides; D003404:Creatinine; D000077425:Fondaparinux