The mechanisms of cyst formation in autosomal dominant polycystic kidney disease (ADPKD) remain incompletely understood, rates of disease progression vary greatly, and effective clinical therapies for ADPKD are not available. Recent evidence indicates that aberrations of specific epigenetic regulators, such as histone deacetylase and histone methyltransferase, promote cyst growth through regulating different PKD-associated pathways in ADPKD. The epigenetic regulator, bromodomain-containing protein 4 (BRD4) binds preferentially to acetylated lysine residues in histones, which can regulate gene transcription by recruiting positive transcription elongation factor beta and initiation cofactor. The objective of the proposed Kansas Institute for Precision Medicine COBRE Project 3 is to understand the functional roles of Brd4 in ADPKD. Our preliminary studies indicated that Brd4 was upregulated in Pkd1 mutant renal epithelial cells and tissues, and that treatment with bromodomain inhibitor JQ1 delayed cyst growth in Pkd1 conditional knockout mice through regulating c-Myc/p21 pathway. In addition, JQ1 treatment decreased interstitial fibrosis in the cystic kidneys and prevented TGF-?1 induced expression of fibrotic genes in renal fibroblasts. Thus, we hypothesize that BRD4 acts as a crucial transcriptional regulator of cyst formation and fibroblast activation, and targeting BRD4 may delay renal cyst growth and interstitial fibrosis in some patients with ADPKD. We will test this hypothesis with three specific aims.
In Specific Aim 1, we will investigate whether genetic deletion and pharmaceutically inhibition of BRD4 slow PKD progression in ADPKD mouse models in vivo.
In Specific Aim 2, we will investigate the transcriptional mechanisms by which BRD4 drives chromatin-dependent signal transduction and selective gene control during cyst progression through Chip-seq and RNA-seq. We will establish a novel method to isolate the renal epithelial cells from blood of ADPKD patient, in order to validate the novel pathways that are regulated by Brd4 and identify individuals with activation of this pathway that would be likely to respond to therapy.
In Specific Aim 3, we will define the mechanisms by which BRD4 directs the fibrotic response in renal fibroblasts. This is the first study to define the functional roles of Brd4 and Brd4-mediated signaling pathways in cyst development and interstitial fibrosis in ADPKD, which will not only further our understanding of cyst development but also identify patients with activation of this pathway and provide a rationale for using Brd4 inhibitor as a targeted therapy for ADPKD.