Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition

Guangtao Zhang, Ruijie Liu, Yifei Zhong, Alexander N Plotnikov, Weijia Zhang, Lei Zeng, Elena Rusinova, Guillermo Gerona-Nevarro, Natasha Moshkina, Jennifer Joshua, Peter Y Chuang, Michael Ohlmeyer, John Cijiang He, Ming-Ming Zhou
Journal of Biological Chemistry 2012 August 17, 287 (34): 28840-51
NF-κB-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-κB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-κB transcriptional activity by small molecule blocking NF-κB 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-κB, effectively attenuates NF-κB transcriptional activation of proinflammatory genes in kidney cells treated with TNFα 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-κB, represents a new therapeutic approach for treating NF-κB-mediated inflammation and kidney injury in HIVAN.

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