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

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-B pathway, a key inflammatory signaling pathway. The RelA NF-B subunit is activated by acetylation of lysine 310. In damaged kidneys and cytokine–stimulated renal cells, JQ1 reduced the nuclear levels of RelA NF-B. 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-B 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.

Source: Journal of the American Society of Nephrology : JASN - January 30, 2017 Category: Urology & Nephrology Authors: Suarez-Alvarez, B., Morgado-Pascual, J. L., Rayego-Mateos, S., Rodriguez, R. M., Rodrigues-Diez, R., Cannata-Ortiz, P., Sanz, A. B., Egido, J., Tharaux, P.-L., Ortiz, A., Lopez-Larrea, C., Ruiz-Ortega, M. Tags: Basic Research Source Type: research