Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10799155 | Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | 2014 | 11 Pages |
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.
Keywords
SFNESDRUACRTGFβ1NQO1GFRGBMECMNACNrf2DMEMFBSkeap1Dulbecco's modified Eagle MediumN-acetylcysteineROSSp1Urine Albumin to Creatinine RatioEnd-stage renal diseaseTransforming growth factor-β1c-JunDiabetes mellitusfetal bovine serumSulforaphaneglomerular basement membranenuclear factor erythroid 2-related factor 2FibronectinExtracellular matrixSpecificity protein 1Glomerular filtration rateDiabetic nephropathyPASAREhematoxylin-eosinReactive oxygen species
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Authors
Pan Gao, Liliang Li, Lili Ji, Yingze Wei, Hui Li, Guoguo Shang, Zhonghua Zhao, Qi Chen, Tao Jiang, Nong Zhang,