Roles of Coagulation Pathway and Factor Xa in the Progression of Diabetic Nephropathy in db/db Mice
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概要
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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.
- 公益社団法人 日本薬学会の論文
著者
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MIZUKAMI Hajime
Department of Legal Medicine, Asahikawa Medical College
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ONO Takahiko
Department of Nephrology, Shizuoka General Hospital
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MAKINO Toshiaki
Department of Kampo Medicinal Science, Hokkaido College of Pharmacy
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Ono Takahiko
Department Of Cardiovascular Medicine Kyoto University Graduate School Of Medicine
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SUMI Ayaka
Department of Applied Biological Sciences, Nihon University
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Sumi Ayaka
Department Of Applied Biological Sciences Nihon University
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Makino Toshiaki
Department Of Kampo Medicinal Science Hokkaido College Of Pharmacy
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Yamanaka-Hanada Natsuko
Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka
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Bai Fan
Department of Pharmacognosy, Graduate School of Pharmaceutical Sciences, Nagoya City University
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Mizukami Hajime
Department Of Forensic Medicine Tokyo Medical University
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Makino Toshiaki
Department Of Chemistry Faculty Of Science Okayam University Of Science
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Ono Takahiko
Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka
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Sumi Ayaka
Department of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka
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