Coagulation Factor Xa and Protease-Activated Receptor 2 as Novel Therapeutic Targets for Diabetic Nephropathy

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 36; no. 8; pp. 1525 - 1533
• Main Authors: Oe, Yuji, Hayashi, Sakiko, Fushima, Tomofumi, Sato, Emiko, Kisu, Kiyomi, Sato, Hiroshi, Ito, Sadayoshi, Takahashi, Nobuyuki
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.08.2016
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Blood Coagulation - drug effects; Cell Line; Cytokines - genetics; Cytokines - metabolism; Diabetic Nephropathies - genetics; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Diabetic Nephropathies - prevention & control; Disease Models, Animal; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Factor Xa - drug effects; Factor Xa - genetics; Factor Xa - metabolism; Factor Xa Inhibitors - pharmacology; Genotype; Humans; Inflammation Mediators - metabolism; Insulin - genetics; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice, Knockout; Nitric Oxide Synthase Type III - deficiency; Nitric Oxide Synthase Type III - genetics; Phenotype; Podocytes - drug effects; Podocytes - metabolism; Pyridines - pharmacology; Receptor, PAR-2 - antagonists & inhibitors; Receptor, PAR-2 - deficiency; Receptor, PAR-2 - genetics; Receptor, PAR-2 - metabolism; Signal Transduction - drug effects; Thiazoles - pharmacology; Up-Regulation; cardiovascular diseases; factor Xa; inflammation; prognosis; diabetic nephropathy
• DOI: 10.1161/ATVBAHA.116.307883
• ISSN: 1079-5642; 1524-4636

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.