Nrf2 ameliorates diabetic nephropathy progression by transcriptional repression of TGFβ1 through interactions with c-Jun and SP1

被引:50
作者
Gao, Pan [1 ]
Li, Liliang [2 ]
Ji, Lili [3 ]
Wei, Yingze [1 ]
Li, Hui [1 ]
Shang, Guoguo [1 ]
Zhao, Zhonghua [1 ]
Chen, Qi [1 ]
Jiang, Tao [1 ]
Zhang, Nong [1 ]
机构
[1] Fudan Univ, Dept Pathol, Sch Basic Med Sci, Shanghai 200433, Peoples R China
[2] Fudan Univ, Dept Forens Med, Sch Basic Med Sci, Shanghai 200433, Peoples R China
[3] Nantong Univ, Sch Med, Dept Pathol, Nantong, Jiangsu, Peoples R China
来源
BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS | 2014年 / 1839卷 / 11期
关键词
Nrf2; TGF beta 1; c-Jun; SP1; Diabetic nephropathy; ROS; GROWTH-FACTOR-BETA; OXIDATIVE STRESS; GENE-EXPRESSION; MESANGIAL CELLS; UP-REGULATION; CANCER; MOUSE; MECHANISMS; PREVENTION; ACTIVATORS;
D O I
10.1016/j.bbagrm.2014.06.018
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
Diabetic nephropathy (DN) is one of the major complications in diabetes patients. Reactive oxygen species (ROS) play key roles in DN progression. As a primary transcription factor. Nrf2 controls the antioxidant response to maintain cellular redox homeostasis. Herein we systemically examined the role of Nrf2 in DN progression and its regulatory mechanism in a mouse model bearing type II diabetes and in cultured human renal mesangial cells (HRMCs). We found that Nrf2 could ameliorate DN progression by transcriptional repression of TGF beta 1 in vivo and in vitro. Moreover, Nrf2 bound to the specific region in TGF beta 1 promoter by interactions with transcription factors c-Jun and SPI. Significant abolishment of Nrf2-mediated TGF beta 1 transcriptional repression could be accomplished by knockdown of either c-Jun or SP1, and site-directed mutagenesis of c-Jun and SPI binding sites in the TGF beta 1 promoter specific region. Moreover, after interacting with c-Jun and SP1, Nrf2 inhibited c-Jun and SP1 activations, and thus reversed c-Jun- and SP1-promoted TGF beta 1 transcription. In all, Nrf2 could slow down DN progression by repression of TGF beta 1 in a c-Jun and SPI-dependent way. Our findings may provide novel clues for DN preventions and interventions in clinic. (C) 2014 Elsevier B.V. All rights reserved.
引用
收藏
页码:1110 / 1120
页数:11
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