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Bromodomain and Extraterminal Proteins as Novel Epigenetic Targets for Renal Diseases

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Review

Bromodomain and Extraterminal Proteins as Novel Epigenetic Targets for Renal Diseases

Jose Luis Morgado-Pascual et al. Front Pharmacol.

Abstract

Epigenetic mechanisms, especially DNA methylation and histone modifications, are dynamic processes that regulate the gene expression transcriptional program in normal and diseased states. The bromodomain and extraterminal (BET) protein family (BRD2, BRD3, BRD4, and BRDT) are epigenetic readers that, via bromodomains, regulate gene transcription by binding to acetylated lysine residues on histones and master transcriptional factors. Experimental data have demonstrated the involvement of some BET proteins in many pathological conditions, including tumor development, infections, autoimmunity, and inflammation. Selective bromodomain inhibitors are epigenetic drugs that block the interaction between BET proteins and acetylated proteins, thus exerting beneficial effects. Recent data have described the beneficial effect of BET inhibition on experimental renal diseases. Emerging evidence underscores the importance of environmental modifications in the origin of pathological features in chronic kidney diseases (CKD). Several cellular processes such as oxidation, metabolic disorders, cytokines, inflammation, or accumulated uremic toxins may induce epigenetic modifications that regulate key processes involved in renal damage and in other pathological conditions observed in CKD patients. Here, we review how targeting bromodomains in BET proteins may regulate essential processes involved in renal diseases and in associated complications found in CKD patients, such as cardiovascular damage, highlighting the potential of epigenetic therapeutic strategies against BET proteins for CKD treatment and associated risks.

Keywords: BET proteins; chronic kidney disease; epigenetic modifications; fibrosis; inflammation; renal injury.

Figures

Figure 1
Figure 1
Bromodomain structure in the bromodomain and extraterminal (BET) family proteins.
Figure 2
Figure 2
Bromodomain and extraterminal (BET) proteins recognize acetylated residues in histones or in other proteins such as transcription factors. BET proteins can recruit transcription factors in distant areas from the promoter of genes involved in different cellular processes.
Figure 3
Figure 3
Bromodomain and extraterminal (BET) proteins regulate cellular processes such as cell cycle, proliferation, differentiation, inflammation, and fibrosis. JQ1 binds to BRD4, this situation not allows the recruitment of p65 and finally it is ubiquitinilated and degraded by the proteasome. BRD4 interacts with NF-kB to induce the expression of genes associated with processes such as inflammation or TH17 immune response.
Figure 4
Figure 4
BRD4 is involved in the transforming growth factor β (TGF-ß)/SMAD signaling pathway. BRD4 interacts with the components of this signaling pathway to regulate the expression of genes related to the synthesis of extracellular matrix proteins (MEC) and fibrosis.
Figure 5
Figure 5
Summary of the different bromodomain and extraterminal (BET) modulators in experimental/clinical studies in the context of several diseases including renal disease and the signaling pathways associated. iBETs interact with several signaling pathways to regulate inflammation and fibrosis.

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