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J Am Soc Nephrol. 2017 Feb;28(2):504-519. doi: 10.1681/ASN.2015080910. Epub 2016 Jul 19.

Inhibition of Bromodomain and Extraterminal Domain Family Proteins Ameliorates Experimental Renal Damage.

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Cellular Biology in Renal Diseases Laboratory, Nephrology Department and.
Cellular Biology in Renal Diseases Laboratory, Nephrology Department and
Immunology Department, Hospital Universitario Central de Asturias, REDINREN, Oviedo, Spain.
Nephrology Department, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid, REDINREN, Madrid, Spain.
Anatomy Department, Fundación Jiménez Díaz, Madrid, Spain.
Dialysis Unit, Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Nephrology Department, School of Medicine, Universidad Autónoma Madrid, Renal Research Retics (REDINREN), Madrid, Spain.
IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma Madrid, Madrid, Spain; and.
Paris Cardiovascular Research Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.


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.


Cell Signaling; chemokine; transcription factors

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