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Publication Abstract from PubMed

NF-kappaB-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-kappaB activation, leading to the production of proinflammatory chemokines, cytokines, and adhesion molecules. In this study, we explored selective inhibition of NF-kappaB transcriptional activity by small molecule blocking NF-kappaB 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-kappaB, effectively attenuates NF-kappaB transcriptional activation of proinflammatory genes in kidney cells treated with TNFalpha 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-kappaB, represents a new therapeutic approach for treating NF-kappaB-mediated inflammation and kidney injury in HIVAN.

Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition.,Zhang G, Liu R, Zhong Y, Plotnikov AN, Zhang W, Zeng L, Rusinova E, Gerona-Nevarro G, Moshkina N, Joshua J, Chuang PY, Ohlmeyer M, He JC, Zhou MM J Biol Chem. 2012 Aug 17;287(34):28840-51. Epub 2012 May 29. PMID:22645123^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.