title: Nrf2 ameliorates diabetic nephropathy progression by transcriptional repression of TGFβ1 through interactions with c-Jun and SP1.
abstract: 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 TGFβ1 in vivo and in vitro. Moreover, Nrf2 bound to the specific region in TGFβ1 promoter by interactions with transcription factors c-Jun and SP1. Significant abolishment of Nrf2-mediated TGFβ1 transcriptional repression could be accomplished by knockdown of either c-Jun or SP1, and site-directed mutagenesis of c-Jun and SP1 binding sites in the TGFβ1 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 TGFβ1 transcription. In all, Nrf2 could slow down DN progression by repression of TGFβ1 in a c-Jun and SP1-dependent way. Our findings may provide novel clues for DN preventions and interventions in clinic.
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: 11111010014@fudan.edu.cn.
authors.forename: Pan
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: 11111010016@fudan.edu.cn.
authors.forename: Liliang
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pathology, Medical School of Nantong University, 19 Qixiu Road, Nantong, Jiangsu Province, China. Electronic address: liliji79@ntu.edu.cn.
authors.forename: Lili
authors.initials: L
authors.lastname: Ji
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: 121110081@fudan.edu.cn.
authors.forename: Yingze
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: huili78@fudan.edu.cn.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: 11111010069@fudan.edu.cn.
authors.forename: Guoguo
authors.initials: G
authors.lastname: Shang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: 199752@sina.com.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: smubingli@163.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: taojiangqd@gmail.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pathology, School of Basic Medical Sciences, Fudan University, 138 Yixueyuan Road, Xuhui District, Shanghai, China. Electronic address: nzhang@fudan.edu.cn.
authors.forename: Nong
authors.initials: N
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; D016329:Sp1 Transcription Factor; D053773:Transforming Growth Factor beta1
keywords: Diabetic nephropathy; Nrf2; ROS; SP1; TGFβ1; c-Jun