Protease-activated receptor 2 exacerbates adenine-induced renal tubulointerstitial injury in mice

被引:23
作者
Hayashi, Sakiko [1 ,2 ]
Oe, Yuji [3 ,4 ]
Fushima, Tomofumi [1 ,2 ]
Sato, Emiko [1 ,2 ,3 ]
Sato, Hiroshi [1 ,2 ,3 ]
Ito, Sadayoshi [3 ]
Takahashi, Nobuyuki [1 ,2 ,3 ]
机构
[1] Tohoku Univ, Div Clin Pharmacol & Therapeut, Grad Sch Pharmaceut Sci, Sendai, Miyagi 9808578, Japan
[2] Fac Pharmaceut Sci, Sendai, Miyagi 9808578, Japan
[3] Tohoku Univ, Div Nephrol Endocrinol & Vasc Med, Grad Sch Med, Sendai, Miyagi 9808574, Japan
[4] Tohoku Univ, Div Fetomaternal Med Sci, Dept Community Med Support, Tohoku Med Megabank Org, Sendai, Miyagi 9808574, Japan
基金
美国国家卫生研究院; 日本学术振兴会;
关键词
Renal insufficiency; Coagulation factors; Fibrosis; Inflammation; Oxidative stress; CHRONIC KIDNEY-DISEASE; COAGULATION-FACTOR XA; GROWTH-FACTOR-BETA; DIABETIC-NEPHROPATHY; ENDOTHELIAL-CELLS; FIBROSIS; INFLAMMATION; CONTRIBUTES; PROGRESSION; EXPRESSION;
D O I
10.1016/j.bbrc.2016.12.108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hypercoagulability is associated with chronic kidney disease (CKD). Tissue factor/factor VIIa complex and factor Xa in the coagulation cascade are known to activate proteaseeactivated 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 adenineinduced tubular injury. PAR2 antagonists under development could be useful to treat and prevent CKD. (C) 2016 Elsevier Inc. All rights reserved.
引用
收藏
页码:547 / 552
页数:6
相关论文
共 31 条
[1]   Inflammation and Progression of CKD: The CRIC Study [J].
Amdur, Richard L. ;
Feldman, Harold I. ;
Gupta, Jayanta ;
Yang, Wei ;
Kanetsky, Peter ;
Shlipak, Michael ;
Rahman, Mahboob ;
Lash, James P. ;
Townsend, Raymond R. ;
Ojo, Akinlolu ;
Roy-Chaudhury, Akshay ;
Go, Alan S. ;
Joffe, Marshall ;
He, Jiang ;
Balakrishnan, Vaidyanathapuram S. ;
Kimmel, Paul L. ;
Kusek, John W. ;
Raj, Dominic S. .
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2016, 11 (09) :1546-1556
[2]  
[Anonymous], KIDNEY INT S
[3]   Mitochondrial reactive oxygen species: a common pathway for PAR1-and PAR2-mediated tissue factor induction in human endothelial cells [J].
Banfi, C. ;
Brioschi, M. ;
Barbieri, S. S. ;
Eligini, S. ;
Barcella, S. ;
Tremoli, E. ;
Colli, S. ;
Mussoni, L. .
JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2009, 7 (01) :206-216
[4]   The NOX family of ROS-generating NADPH oxidases: Physiology and pathophysiology [J].
Bedard, Karen ;
Krause, Karl-Heinz .
PHYSIOLOGICAL REVIEWS, 2007, 87 (01) :245-313
[5]   Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis [J].
Chung, Hyunjae ;
Ramachandran, Rithwik ;
Hollenberg, Morley D. ;
Muruve, Daniel A. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (52) :37319-37331
[6]   Prevalence of chronic kidney disease in the United States [J].
Coresh, Josef ;
Selvin, Elizabeth ;
Stevens, Lesley A. ;
Manzi, Jane ;
Kusek, John W. ;
Eggers, Paul ;
Van Lente, Frederick ;
Levey, Andrew S. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2007, 298 (17) :2038-2047
[7]   Reduced Uterine Perfusion Pressure (RUPP) Model of Preeclampsia in Mice [J].
Fushima, Tomofumi ;
Sekimoto, Akiyo ;
Minato, Takahiro ;
Ito, Takuya ;
Oe, Yuji ;
Kisu, Kiyomi ;
Sato, Emiko ;
Funamoto, Kenichi ;
Hayase, Toshiyuki ;
Kimura, Yoshitaka ;
Ito, Sadayoshi ;
Sato, Hiroshi ;
Takahashi, Nobuyuki .
PLOS ONE, 2016, 11 (05)
[8]   Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization [J].
Go, AS ;
Chertow, GM ;
Fan, DJ ;
McCulloch, CE ;
Hsu, CY .
NEW ENGLAND JOURNAL OF MEDICINE, 2004, 351 (13) :1296-1305
[9]   Protease-activated receptor-2 expression in IgA nephropathy: A potential role in the pathogenesis of interstitial fibrosis [J].
Grandaliano, G ;
Pontrelli, P ;
Cerullo, G ;
Monno, R ;
Ranieri, E ;
Ursi, M ;
Loverre, A ;
Gesualdo, L ;
Schena, FP .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2003, 14 (08) :2072-2083
[10]   3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13-USAG-1 pathway [J].
Hamasaki, Yoshifumi ;
Doi, Kent ;
Okamoto, Koji ;
Ijichi, Hideaki ;
Seki, George ;
Maeda-Mamiya, Rui ;
Fujita, Toshiro ;
Noiri, Eisei .
LABORATORY INVESTIGATION, 2012, 92 (08) :1161-1170