Histone acetylation generally favors gene expression and it has been extensively studied in renal injury. Global changes in kidney histone acetylation were observed in experimental AKI (e.g. IRI, endotoxemia) and CKD (UUO, diabetic nephropathy). Histone acetylation increased during renal injury in most animal models analyzed (endotoxemia, UUO, diabetic nephropathy in db/db mice) (Sayyed et al., 2010; Huang et al., 2015; Hewitson et al., 2017). During ischemia reperfusion injury (IRI), histone acetylation presents a more complex regulation, it is transiently decreased during ischemia, but it recovers, or even increases, after reperfusion, and may persist increased for 3 weeks (Marumo et al., 2008; Zager et al., 2011). The impact of histone acetylation over the expression of specific relevant genes in AKI has been also studied, including the nephroprotective genes PGC1α and Klotho, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and the inflammatory cytokine Interleukine-6 (IL-6), among others (Naito et al., 2009; Li et al., 2010; Ruiz-Andres et al., 2016b). The functional contribution of histone acetylation to kidney injury is supported by numerous preclinical studies in AKI (e.g. cisplatin, IRI) and CKD [e.g. UUO, polycystic kidney disease (PKD), diabetic nephropathy] models, and HDAC inhibitors were frequently nephroprotective (Fontecha-Barriuso et al., 2018). Related with histone acetylation, another emergent line of research is the study of the bromodomain and extraterminal (BET) protein family. BET proteins are readers that bind to acetylated lysines of histones and facilitate binding of transcription factors. BET targeting has been beneficial in preclinical kidney disease and ongoing clinical trials of the BET inhibitor apabetalone explore kidney function as a secondary outcome (Suarez-Alvarez et al., 2017; Fontecha-Barriuso et al., 2018).
These data show the complex regulation of epigenetic modifications in kidney diseases. The overall pattern of the different DNA and histone marks suggests that epigenetic modifications could favor the differential gene expression observed in kidney disease, opening the door for therapeutic strategies targeting epigenetic modulation.