Down-regulation of NF-?B transcriptional activity in HIV-associated kidney disease by BRD4 inhibition.

ABSTRACT: NF-?B-mediated inflammation is the major pathology in chronic kidney diseases, including HIV-associated nephropathy (HIVAN) that ultimately progresses to end stage renal disease. HIV infection in the kidney induces NF-?B activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-?B transcriptional activity by small molecule blocking NF-?B binding to the transcriptional cofactor BRD4, which is required for the assembly of the productive transcriptional complex comprising positive transcription elongation factor b and RNA polymerase II. We showed that our BET (Bromodomain and Extra-Terminal domain)-specific bromodomain inhibitor MS417, designed to block BRD4 binding to the acetylated NF-?B, effectively attenuates NF-?B transcriptional activation of proinflammatory genes in kidney cells treated with TNF? or infected by HIV. MS417 ameliorates inflammation and kidney injury in HIV-1 transgenic mice, an animal model for HIVAN. Our study suggests that BET bromodomain inhibition, targeting at the proinflammatory activity of NF-?B, represents a new therapeutic approach for treating NF-?B-mediated inflammation and kidney injury in HIVAN.

SUBMITTER: Zhang G 

PROVIDER: S-EPMC3436579 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature