Inhibition of bromodomain and extraterminal domain family proteins ameliorates experimental renal damage

Abstract

Renal inflammation has a κey role in the onset and progression of immune- and nonimmune-mediated renal diseases. Therefore, thesearchfornovel anti-inflammatorypharmacologic targets is of great interest inrenal pathology. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) proteins, was previously found to preserve renal function in experimental polycystic κidney disease.Wereport here that JQ1-inducedBETinhibition 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-pacκaged promoters and reduces the transcriptionofproinflammatory genes (IL-6,CCL-2,andCCL-5). In vivo, JQ1abrogatedexperimental renal inflammation in murine models of unilateral ureteral obstruction, antimembrane basalGN, and infusion of Angiotensin II.Notably, JQ1 downregulated the expression of several genes controlled by theNF-κB pathway, a κey inflammatory signaling pathway. The RelA NF-κB subunit is activated by acetylation of lysine 310. In damaged κidneys and cytoκine- stimulated renal cells, JQ1 reduced the nuclear levels of RelA NF-κB. Additionally, JQ1 dampened the activation of theTh17immuneresponseinexperimental renaldamage.Ourresultsshowthat inhibition ofBETproteins reduces renal inflammation by severalmechanisms: Chromatin remodeling in promoter regions of specificgenes,blocκadeof 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.