Yuji Oe1, Sakiko Hayashi1, Tomofumi Fushima1, Emiko Sato1, Kiyomi Kisu1, Hiroshi Sato1, Sadayoshi Ito1, Nobuyuki Takahashi2. 1. 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.). 2. 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.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
Authors: Feng Li; Tomofumi Fushima; Gen Oyanagi; H W Davin Townley-Tilson; Emiko Sato; Hironobu Nakada; Yuji Oe; John R Hagaman; Jennifer Wilder; Manyu Li; Akiyo Sekimoto; Daisuke Saigusa; Hiroshi Sato; Sadayoshi Ito; J Charles Jennette; Nobuyo Maeda; S Ananth Karumanchi; Oliver Smithies; Nobuyuki Takahashi Journal: Proc Natl Acad Sci U S A Date: 2016-11-07 Impact factor: 11.205
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Arnold C Spek; Maaike Waasdorp; JanWillem Duitman; Sandrine Florquin; C Arnold Spek Journal: Am J Transl Res Date: 2017-10-15 Impact factor: 4.060