Inhibition of bromodomain and extraterminal domain family proteins ameliorates experimental renal damage
Entity
UAM. Departamento de MedicinaPublisher
American Society of NephrologyDate
2017Citation
10.1681/ASN.2015080910
Journal of the American Society of Nephrology 28.2 (2017): 504-519
ISSN
1533-3450 (online); 1046-6673 (print)DOI
10.1681/ASN.2015080910Funded by
The bromodomain and extraterminal inhibitor JQ1 was provided collaboratively by Dr. James Bradner (Dana-Farber Cancer Institute, Boston, MA). This work was supported by the Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional grants PI014/0041, PI13/00047, and PI12/02587; Red de Investigación Renal grants RD12/0021/0002, RD12/0021/0021, RD12/0021/001, and RD16/009; Comunidad de Madrid Fibroteam grants S2010/BMD-2321 and S2010/ BMD-2378; Plan de Ciencia, Tecnología e Innovación 2013–2017 del Principado de Asturias, grant GRUPIN-14-030; and the Instituto Reina Sofía de Investigación en Nefrología. B.S.-A. was supported by Sara Borrell, A.B.S. was supported by Miguel Servet, and A.O. and C.L.-L. were supported by Intensificación Instituto de Salud Carlos IIIProject
Gobierno de España. PI014/0041; Gobierno de España. PI19-00584; Gobierno de España. PI12/02587; Comunidad de Madrid. S2010/BMD-2321; Comunidad de Madrid. S2010/ BMD-2378Subjects
MedicinaRights
© 2017 by the American Society of NephrologyAbstract
Renal inflammation has a key role in the onset and progression of immune– and nonimmune–mediated renal diseases. Therefore, the search for novel anti–inflammatory pharmacologic targets is of great interest in renal pathology. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) proteins, was previously found to preserve renal function in experimental polycystic kidney disease. We report here that JQ1–induced BET inhibition modulated the in vitro expression of genes involved in several biologic processes, including inflammation and immune responses. Gene silencing of BRD4, an important BET protein, and chromatin immunoprecipitation assays showed that JQ1 alters the direct association of BRD4 with acetylated histone–packaged promoters and reduces the transcription of proinflammatory genes (IL-6, CCL-2, and CCL-5). In vivo, JQ1 abrogated experimental renal inflammation in murine models of unilateral ureteral obstruction, antimembrane basal GN, and infusion of Angiotensin II. Notably, JQ1 downregulated the expression of several genes controlled by the NF-κB pathway, a key inflammatory signaling pathway. The RelA NF-κB subunit is activated by acetylation of lysine 310. In damaged kidneys and cytokine–stimulated renal cells, JQ1 reduced the nuclear levels of RelA NF-κB. Additionally, JQ1 dampened the activation of the Th17 immune response in experimental renal damage. Our results show that inhibition of BET proteins reduces renal inflammation by several mechanisms: chromatin remodeling in promoter regions of specific genes, blockade of NF-κB pathway activation, and modulation of the Th17 immune response. These results suggest that inhibitors of BET proteins could have important therapeutic applications in inflammatory renal diseases
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Google Scholar:Suarez-Alvarez, Beatriz
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Morgado-Pascual, José Luis
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Rayego Mateos, Sandra
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Rodríguez, Ramón M.
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Rodrigues Díez, Raúl
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Cannata Ortiz, Pablo Javier
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Sanz, Ana B.
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Egido, Jesús
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Tharaux, Pierre-Louis
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Ortiz Arduán, Alberto
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Lopez-Larrea, Carlos
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Ruiz Ortega, Marta
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