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.
[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.
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