Nrf2 ameliorates diabetic nephropathy progression by transcriptional repression of TGF beta 1 through interactions with c-Jun and SP1

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 SP1. 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 SP1 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 SP1-dependent way. Our findings may provide novel clues for DN preventions and interventions in clinic.