Synergistic effects of c-Jun and SP1 in the promotion of TGFβ1-mediated diabetic nephropathy progression.
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.
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.
Pan
P
Gao
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
Yingze
Y
Wei
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
Zhigang
Z
Zhang
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
Wenjiao
W
Zeng
Forensic Science Center, East China University of Political Science and Law, 112 Huayang Road, Changning District, Shanghai 200042, China.
Daming
D
Sun
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
Danyang
D
Liu
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
Bo
B
Hou
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
Congying
C
Zhang
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China.
Nong
N
Zhang
Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai 200032, China. Electronic address: huili78@fudan.edu.cn.
Hui
H
Li
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.
Liliang
L
Li
D000328:Adult; D000368:Aged; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D000873:Anthracenes; D016755:Proto-Oncogene Proteins c-jun; D016329:Sp1 Transcription Factor; D053773:Transforming Growth Factor beta1; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose
Diabetic nephropathy; Phosphorylation; SP1; Synergy; TGFβ1; c-Jun