期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 34, 页码 28840-28851出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.359505
关键词
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资金
- National Institutes of Health [HG004508, DK088541]
- Veterans Affairs Merit Award [1I01BX000345]
NF-kappa 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-kappa B activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-kappa B transcriptional activity by small molecule blocking NF-kappa 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-kappa B, effectively attenuates NF-kappa B transcriptional activation of proinflammatory genes in kidney cells treated with TNF alpha 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-kappa B, represents a new therapeutic approach for treating NF-kappa B-mediated inflammation and kidney injury in HIVAN.
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