Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy.
The role of hypercoagulability in the pathogenesis of diabetic nephropathy (DN) remains elusive. We recently reported the increased infiltration of macrophages expressing tissue factor in diabetic kidney glomeruli; tissue factor activates coagulation factor X (FX) to FXa, which in turn stimulates protease-activated receptor 2 (PAR2) and causes inflammation.



Here, we demonstrated that diabetes mellitus increased renal FX mRNA, urinary FXa activity, and FX expression in glomerular macrophages. Administration of an oral FXa inhibitor, edoxaban, ameliorated DN with concomitant reductions in the expression of PARs (Par1 and Par2) and of proinflammatory and profibrotic genes. Diabetes mellitus induced PAR2, and lack of Par2 ameliorated DN. FXa or PAR2 agonist increased inflammatory cytokines in endothelial cells and podocytes in vitro.



We conclude that enhanced FXa and PAR2 exacerbate DN and that both are promising targets for preventing DN. Alleviating inflammation is probably more important than inhibiting coagulation per se when treating kidney diseases using anticoagulants.
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.).
Yuji
Y
Oe
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.).
Sakiko
S
Hayashi
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.).
Tomofumi
T
Fushima
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.).
Emiko
E
Sato
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.).
Kiyomi
K
Kisu
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.).
Hiroshi
H
Sato
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.).
Sadayoshi
S
Ito
From the Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (Y.O., E.S., K.K., H.S., S.I., N.T.); and Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai, Japan (S.H., T.F., E.S., H.S., N.T.). ntakaha@m.tohoku.ac.jp.
Nobuyuki
N
Takahashi
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015951:Factor Xa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D065427:Factor Xa Inhibitors / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000235:genetics; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics; D010641:Phenotype; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D065427:Factor Xa Inhibitors; D018836:Inflammation Mediators; C561967:Ins2 protein, mouse; D007328:Insulin; D011725:Pyridines; D044464:Receptor, PAR-2; D013844:Thiazoles; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D015951:Factor Xa; C552171:edoxaban
cardiovascular diseases; diabetic nephropathy; factor Xa; inflammation; prognosis