Dipyridamole inhibits cobalt chloride-induced osteopontin expression in NRK52E cells

被引:7
作者
Chen, Tso-Hsiao [2 ,3 ]
Chang, Chia-Fang [1 ,5 ]
Yu, Shu-Chuan [4 ]
Wang, Jiueng-Chueng [4 ]
Chen, Cheng-Hsien [2 ]
Chan, Paul [2 ]
Lee, Horng-Mo [1 ,4 ,5 ]
机构
[1] Taipei Med Univ, Grad Inst Med Sci, Taipei 110, Taiwan
[2] Taipei Med Univ, Wan Fang Hosp, Dept Internal Med, Taipei 110, Taiwan
[3] Taipei Med Univ, Grad Inst Clin Med, Taipei 110, Taiwan
[4] Taipei Med Univ, Wan Fang Hosp, Dept Lab Med, Taipei 110, Taiwan
[5] Taipei Med Univ, Dept Med, Lab Sci & Biotechnol, Taipei 110, Taiwan
关键词
Osteopontin; Dipyridamole; Heme oxygenase-1; NRK52E tubular cell; ACTIVATED PROTEIN-KINASE; INTERSTITIAL FIBROSIS; GENE-EXPRESSION; CYCLOSPORINE NEPHROTOXICITY; EPITHELIAL-CELLS; ANGIOTENSIN-II; KNOCKOUT MICE; UP-REGULATION; TGF-BETA; PROLIFERATION;
D O I
10.1016/j.ejphar.2009.03.063
中图分类号
R9 [药学];
学科分类号
100702 [药剂学];
摘要
Osteopontin plays a pivotal role in the progression of interstitial fibrosis in renal ischemia. In the present study, rat renal tubular NRK52E cells treated with hypoxia mimetic cobalt chloride (CoCl2) increased osteopontin production, and are associated with increased phosphorylation of Akt/PKB (protein kinase B) and p38 mitogen-activated protein kinase (p38MAPK). Furthermore, pretreatment of cells with l-N-acetylcysteine (an antioxidant) inhibited CoCl2-stimulated osteopontin protein expression and p38MAPK phosphorylation, but not Akt/PKB phosphorylation. Pretreatment of cells with anti-inflammatory agents celecoxib, tanshinone IIA, and dipyridamole inhibited CoCl2-induced osteopontin production paralleled by heme oxygenase-1 (HO-1) induction. Pretreatment of cells with tin protoporphyrin (a HO-1 inhibitor) or hemoglobin (a carbon monoxide scavenging agent) reversed dipyridamole inhibition of osteopontin expression. Moreover, transfection of HO-1 small interfering RNA (siRNA) reduced dipyridamole-stimulated mitogen-activated protein kinase phosphatase-1 (MKP-1) phosphorylation. Conversely, MKP-1 knockdown reversed dipyridamole inhibition of osteopontin expression. Taken together, these data suggest that dipyridamole may inhibit CoCl2-induced osteopontin expression through HO-1 induction. Increased HO-1 may catalyze the conversion of heme into carbon monoxide, in turn carbon monoxide activates MKP-1. MKP-1 activation inhibits the p38MAPK signaling pathway that mediates CoCl2-induced osteopontin production. (C) 2009 Elsevier B.V. All rights reserved.
引用
收藏
页码:10 / 18
页数:9
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