Roles of coagulation pathway and factor Xa in the progression of diabetic nephropathy in db/db mice.

Abstract

The active type of coagulation factor X (factor Xa) activates various cell-types through protease-activated receptor 2 (PAR2). We previously reported that a factor Xa inhibitor could suppress Thy-1 nephritis. Considering that fibrin deposition is observed in diabetic nephropathy as well as in glomerulonephritis, this study examined the roles of the coagulation pathway and factor Xa in the development of diabetic nephropathy using type 2 diabetic model mice. Diabetic (db/db) and normoglycemic (m+/m+) mice were immunohistochemically evaluated for their expression/deposition of PAR2, transforming growth factor (TGF)-β, fibrin, extracellular matrix (ECM) proteins, and CD31 at week 20. Significantly greater numbers of PAR2-positive cells and larger amounts of fibronectin, and collagen IV depositions were observed in the glomeruli of db/db mice than those in m+/m+ mice. Next, expression of PAR2 versus deposition of collagen IV and fibronectin was compared between week 20 and week 30, and the number of PAR2-positive cells in the glomeruli decreased in contrast with the increased accumulation of ECM proteins. In an intervention study, fondaparinux, a factor Xa inhibitor, was subcutaneously administered for ten weeks from week 10 to 20. Fondaparinux treatment significantly suppressed urinary protein, glomerular hypertrophy, fibrin deposition, expression of connective tissue growth factor, and ECM proteins deposition together with CD31-positive capillaries. These results suggest that coagulation pathway and glomerular PAR2 expression are upregulated in the early phase of diabetes, together with the increase of profibrotic cytokines expression, ECM proteins deposition and CD-31-positive vessels. Factor Xa inhibition may ameliorate glomerular neoangiogenesis and ECM accumulation in diabetic nephropathy.

• Authors: Ayaka Sumi, Natsuko Yamanaka-Hanada, Fan Bai, Toshiaki Makino, Hajime Mizukami, Takahiko Ono
• Journal: Biological & pharmaceutical bulletin (Biol Pharm Bull) Vol. 34 Issue 6 Pg. 824-30 ( 2011) ISSN: 1347-5215 [Electronic] Japan
• PMID: 21628879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticoagulants
• Extracellular Matrix Proteins
• Factor Xa Inhibitors
• Platelet Endothelial Cell Adhesion Molecule-1
• Polysaccharides
• Receptor, PAR-2
• Transforming Growth Factor beta
• Fibrin
• Factor Xa
• Fondaparinux

Topics

• Animals
• Anticoagulants (therapeutic use)
• Blood Coagulation
• Capillaries (drug effects, metabolism, pathology)
• Diabetes Mellitus, Type 2 (complications)
• Diabetic Nephropathies (drug therapy, metabolism, pathology, physiopathology)
• Disease Progression
• Extracellular Matrix Proteins (metabolism)
• Factor Xa (metabolism)
• Factor Xa Inhibitors
• Fibrin (metabolism)
• Fondaparinux
• Hypertrophy (prevention & control)
• Kidney (drug effects, metabolism, pathology, physiopathology)
• Kidney Glomerulus (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Obese
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Polysaccharides (therapeutic use)
• Proteinuria (prevention & control)
• Receptor, PAR-2 (metabolism)
• Transforming Growth Factor beta (metabolism)
• Up-Regulation (drug effects)