期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 702, 期 1-3, 页码 208-217出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2013.01.031
关键词
Glomerular mesangial cell; Isolated glomerulus; Renin angiotensin system; Reactive oxygen species; p102; Transforming growth factor-beta 1
资金
- Natural Science Foundation of China [81070577, 81170636, 81000280]
P102 is a multifunctional transcriptional co-activator. This experiment is designed to investigate the role of p102 in the activation of renin-angiotensin system (RAS) and sequentially extracellular matrix (ECM) over synthesis in diabetic nephropathy. Rat glomerular mesangial cells (MCs) or isolated glomeruli were cultured in normal glucose (NG, 5.5 mM) or high glucose (HG, 25 mM) DMEM. The generation of reactive oxygen species was measured by 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe assay. The protein levels were analyzed by Western blot and the mRNA levels were evaluated by real-time PCR. HG treatment induced an increase in reactive oxygen species production. Culturing the cells in HG for 48 h, p102 mRNA and protein, angiotensin II type 1 receptor (AT(1) receptor) mRNA, transforming growth factor-beta 1 (TGF-beta 1) and fibronectin proteins were significantly increased. NADPH oxidase inhibitor DPI blocked the HG-induced p102, TGF-beta 1 and fibronetcin elevations. Knockdown on p102 expression by siRNA depressed the HG-induced AT(1) receptor up-regulation as well as the increases in TGF-beta 1 and fibronectin. In contrast, AT(1) receptor antagonist candesartan did not influence p102 levels under either NG or HG condition, but blocked the HG-induced TGF-beta 1 and fibronectin increases. The results from isolated glomeruli were consistent with that of MCs, which showed that HG exposure stimulated the expression of p102. These results suggest that the overproduction of reactive oxygen species at the early stage of HG incubation stimulates p102 synthesis, which in turn up-regulates AT(1) receptor expression. The activation of RAS stimulates TGF-beta 1 and fibronectin production, which further results in ECM accumulation. (C) 2013 Elsevier B.V. All rights reserved.
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