Elevated transcriptional co-activator p102 mediates angiotensin II type 1 receptor up-regulation and extracellular matrix overproduction in the high glucose-treated rat glomerular mesangial cells and isolated glomeruli

被引：10

作者：

Wang, Zhen ^{[1
]}

Ni, Jun ^{[1
]}

Shao, Decui ^{[1
]}

Liu, Jia ^{[1
]}

Shen, Yang ^{[1
]}

Zhou, Li ^{[1
]}

Huang, Yu ^{[3
,4
]}

Yu, Chen ^{[5
]}

Wang, Jun ^{[2
]}

Xue, Hong ^{[1
]}

Lu, Limin ^{[1
]}

机构：

[1] Fudan Univ, Shanghai Med Coll, Dept Physiol & Pathophysiol, Shanghai 200032, Peoples R China

[2] Fudan Univ, Shanghai Med Coll, Dept Integrat Med, Shanghai 200032, Peoples R China

[3] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China

[4] Chinese Univ Hong Kong, Inst Vasc Med, Hong Kong, Hong Kong, Peoples R China

[5] Tongji Univ, Sch Med, Tongji Hosp, Dept Nephrol, Shanghai 200120, Peoples R China

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2013年 / 702卷 / 1-3期

关键词：

Glomerular mesangial cell; Isolated glomerulus; Renin angiotensin system; Reactive oxygen species; p102; Transforming growth factor-beta 1; STRUCTURAL-FUNCTIONAL RELATIONSHIPS; PROTEIN P100; ALBUMIN PERMEABILITY; TUDOR; SYSTEM; RNA; PROLIFERATION; INCREASES; COMPLEX; DOMAIN;

D O I：

10.1016/j.ejphar.2013.01.031

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页码：208 / 217

页数：10