Abstract
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.
Highlights
nuclear factor B (NF-B) and BRD4 control proinflammatory gene activation in HIV-associated kidney disease
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
Summary
NF-B and BRD4 control proinflammatory gene activation in HIV-associated kidney disease. 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. The most prominent response of these cells to HIV-1 infection was the production of proinflammatory mediators, including chemokines, cytokines, and adhesion molecules Many of these genes, as suggested by pathway analysis of the microarray data, are mediated by transcriptional activation of nuclear factor B (NF-B). We sought to determine how a BET-specific BrD inhibitor might influence NF-B transcriptional activity in control of the expression of proinflammatory genes in HIV-infected kidney cells and whether and how BrDi might attenuate kidney injury in HIV-1 transgenic mice (Tg26), which is an established animal model for HIVAN.
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