title: Inhibition of Bromodomain and Extraterminal Domain Family Proteins Ameliorates Experimental Renal Damage.
abstract: 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.
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Nephrology Department and.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Suarez-Alvarez
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Nephrology Department and.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Morgado-Pascual
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Nephrology Department and srayego@fjd.es.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rayego-Mateos
authors.affiliation: Immunology Department, Hospital Universitario Central de Asturias, REDINREN, Oviedo, Spain.
authors.forename: Ramon M
authors.initials: RM
authors.lastname: Rodriguez
authors.affiliation: Nephrology Department, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid, REDINREN, Madrid, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: Rodrigues-Diez
authors.affiliation: Anatomy Department, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Cannata-Ortiz
authors.affiliation: Dialysis Unit, Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Nephrology Department, School of Medicine, Universidad Autónoma Madrid, Renal Research Retics (REDINREN), Madrid, Spain.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma Madrid, Madrid, Spain; and.
authors.forename: Jesus
authors.initials: J
authors.lastname: Egido
authors.affiliation: Paris Cardiovascular Research Centre (PARCC), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: Dialysis Unit, Instituto de Investigación Sanitaria (IIS) Fundación Jiménez Díaz, Nephrology Department, School of Medicine, Universidad Autónoma Madrid, Renal Research Retics (REDINREN), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Immunology Department, Hospital Universitario Central de Asturias, REDINREN, Oviedo, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Larrea
authors.affiliation: Cellular Biology in Renal Diseases Laboratory, Nephrology Department and.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology* / Q000627:therapeutic use*; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors* / Q000502:physiology; D004195:Disease Models, Animal; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use*; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D002868:Chromosomal Proteins, Non-Histone; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C518475:BRDT protein, mouse; D000092468:Bromodomain Containing Proteins; C490844:Brd2 protein, mouse; C518476:Brd3 protein, mouse; C486694:Brd4 protein, mouse
keywords: Cell Signaling; chemokine; transcription factors