title: Protease-activated receptor 2 exacerbates adenine-induced renal tubulointerstitial injury in mice.
abstract: Hypercoagulability is associated with chronic kidney disease (CKD). Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade are known to activate protease-activated receptor 2 (PAR2), and to cause inflammation and tissue injury. Although PAR2 is highly expressed in the kidney, it is unclear whether PAR2 plays a pathogenic role in CKD. To test this, we fed the mice lacking Par2 (F2rl1-/-) and wild type (F2rl1+/+) mice with adenine diet to induce tubulointerstitial injury, a hallmark of CKD. Adenine-treated mice showed severe renal dysfunction, tubular atrophy, and fibrosis. Fibrin deposition and the expression of tissue factor and PARs markedly increased in their kidneys. Lack of Par2 attenuated renal histological damage and reduced the expression levels of genes related to inflammation, fibrosis, and oxidative stress. Our data indicate that PAR2 is critically important in the pathogenesis of adenine-induced tubular injury. PAR2 antagonists under development could be useful to treat and prevent CKD.
authors.affiliation: Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai 980-8578, Japan.
authors.forename: Sakiko
authors.initials: S
authors.lastname: Hayashi
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Oe
authors.affiliation: Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai 980-8578, Japan.
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Fushima
authors.affiliation: Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai 980-8578, Japan; Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Sato
authors.affiliation: Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai 980-8578, Japan; Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.affiliation: Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Division of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Sciences & Faculty of Pharmaceutical Sciences, Sendai 980-8578, Japan; Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan. Electronic address: ntakaha@m.tohoku.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D000225:Adenine / Q000378:metabolism*; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D005165:Factor V / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D007249:Inflammation; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D044464:Receptor, PAR-2 / Q000378:metabolism*; D051436:Renal Insufficiency, Chronic / Q000473:pathology; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D044464:Receptor, PAR-2; C022475:prothrombinase complex; D005165:Factor V; D005337:Fibrin; D013925:Thromboplastin; D015951:Factor Xa; D000225:Adenine
keywords: Coagulation factors; Fibrosis; Inflammation; Oxidative stress; Renal insufficiency