Down-regulation of NF-κB transcriptional activity in HIV-associated kidney disease by BRD4 inhibition.
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.
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Guangtao
G
Zhang
Ruijie
R
Liu
Yifei
Y
Zhong
Alexander N
AN
Plotnikov
Weijia
W
Zhang
Lei
L
Zeng
Elena
E
Rusinova
Guillermo
G
Gerona-Nevarro
Natasha
N
Moshkina
Jennifer
J
Joshua
Peter Y
PY
Chuang
Michael
M
Ohlmeyer
John Cijiang
JC
He
Ming-Ming
MM
Zhou
D016263:AIDS-Associated Nephropathy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000215:Acylation; D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012319:RNA Polymerase II / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse