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Exp Mol Pathol. 2016 Jun;100(3):441-50. doi: 10.1016/j.yexmp.2016.04.005. Epub 2016 Apr 22.

Synergistic effects of c-Jun and SP1 in the promotion of TGFβ1-mediated diabetic nephropathy progression.

Author information

1
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China; Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA.
2
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
3
Forensic Science Center, East China University of Political Science and Law, 112 Huayang Road, Changning District, Shanghai 200042, China.
4
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China. Electronic address: huili78@fudan.edu.cn.
5
Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China. Electronic address: 11111010016@fudan.edu.cn.

Abstract

Diabetic nephropathy (DN) is a major complication of diabetes mellitus. Transforming growth factor beta 1 (TGFβ1) is a well-distinguished mediator of progressive renal fibrosis in DN. However, the molecular mechanisms contributing to enhanced TGFβ1 expression in the progression of DN are not fully understood. Herein, we reported that c-Jun and specificity protein 1 (SP1) were critical upstream regulators of TGFβ1 expression in DN. The increase in c-Jun and SP1 expressions was positively correlated with TGFβ1 in both high glucose-treated human renal mesangial cells (HRMCs) and diabetic kidneys. Furthermore, c-Jun dose-dependently promoted SP1-mediated TGFβ1 transcription and vice versa. The synergistic effects of c-Jun and SP1 were attributed to their auto-regulation and cross-activation. Moreover, enhanced phosphorylation levels of c-Jun and SP1 were accompanied with increased TGFβ1 expression in diabetic kidneys. Accordingly, dephosphorylation of c-Jun and SP1 by the specific c-Jun N-terminal kinase (JNK) inhibitor SP600125 prevented the increase in TGFβ1 expression. These results suggested that c-Jun and SP1 synergistically activated profibrotic TGFβ1 expression in the development of DN by auto-regulation, cross-activation and phospho-modification.

KEYWORDS:

Diabetic nephropathy; Phosphorylation; SP1; Synergy; TGFβ1; c-Jun

PMID:
27112839
DOI:
10.1016/j.yexmp.2016.04.005
[Indexed for MEDLINE]

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