Epigenetic Modification Mechanisms Involved in Inflammation and Fibrosis in Renal Pathology.
The term "epigenetics" was first used by Conrad Waddington in 1942 to describe the effect of gene-environment interactions on the expression of particular phenotypes [1-3]. Not only does gene expression depend on the different changes in the cellular machinery surrounding DNA expression but also the environment exerts a powerful influence on the gene expression. It can be said that epigenetic changes influence the gene expression, but it is only a part of the variability that exists in a cell when it comes to expressing information contained in DNA. Epigenetic mechanisms are fundamental for normal development and maintenance of tissue-specific gene expression through changes on chromatin structure, function regulation, and posttranscriptional mechanisms. These epigenetic modifications include DNA methylation (cytosine methylation), histone posttranslational modifications, and miRNAs (Figure 1) .
Epigenetics has recently been shown to have impact on human health and disease susceptibility. Although there is a genetic predisposition for the development of chronic kidney disease (CKD), genetics alone falls short of explaining the complex disease progression across individual CKD patients . Many factors altered in CKD patients, such as uremic toxins, oxidative stress, and inflammation, as well as changes in metabolic states, like hyperglycemia in diabetes, can induce epigenetic modifications by regulating gene expression and altering the immune response and therefore contribute to renal disease progression . The identification of these epigenetic changes is a recent and innovative field of research in renal pathology . In this review, we summarize the epigenetic mechanisms that could regulate critical processes in renal pathology, including inflammation and extracellular matrix accumulation (ECM), and offer an account of potential therapeutic strategies based on epigenetic targets for CKD treatment (Figure 1).
1.1. DNA Methylation and Kidney Diseases. DNA methylation is a common epigenetic mechanism used by cells to express or silence a gene . DNA methylation mainly occurs on the cytosine residues of CpG (cytosine-phosphate-guanine) sites , and in mammalians, 60-90% of them are methylated . DNA methylation patterns are specific of tissue/cell type maintaining gene expression states . Thus, as a paradigm, hypomethylated DNA is associated with active transcription, whereas hypermethylated DNA is packaged in inactive chromatin (heterochromatin) .
DNA methylation is catalyzed by a family of enzymes named DNA methyltransferases (DNMTs), which transfer a methyl group from S-adenosyl methionine (SAM) to the fifth carbon of cytosine at the dinucleotide CpG. DNMTs can be classified in two groups: (1) maintenance DNMTs such as DNMT1, which shows a preference for hemimethylated DNA and functions during DNA replication, and (2) de novo DNMTs including DNMT3A and DNMT3B, which methylate DNA (unmethylated or methylated) at an equal rate [13-15]. In addition, DNA demethylation can occur passively or as a result of the action of enzyme dioxygenases from the TET protein family (TET1, TET2, and TET3) that generate sequential DNA methylation cytosine changes, such as 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), culminating in excision by base-excision repair of glycosylases such as TDGs (thymine DNA glycosylases), followed by DNA repair to replace the modified cytosines by nonmethylated cytosines .
In the pathological context, aberrant DNA methylation and consequent deregulated gene expression could be involved with the pathogenesis of many diseases, including cancer, cardiovascular pathologies, metabolic disorders (obesity and diabetes mellitus), or renal diseases [17-21]. In the last years, several studies carried out in CKD patients revealed that systemic DNA methylation patterns correlate with the rate of kidney function decline [22, 23].
A recent epigenome-wide association study (EGWAS) in whole-blood DNA of patients from Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies, analyzed using regression models with residualized methylation [beta]-values as the independent variable, showed a statistically significant association between the DNA methylation level in specific CpG sites (e.g., cg23597162 in JAZF1; cg19942083 in PTPN6/PHB2; and cg17944885 in ZNF788/ ZNF20) and the reduction in glomerular filtration rate (eGFR), prevalence and incidence of CKD (cg17944885 and cg19942083 in PTPN6/PHB2), or renal fibrosis (cg12065228 in PQLC2, intergenic cg19942083 near PTPN6/PHB2, cg12116137 in PRPF8, cg09022230 in TNRC18, and cg27660627 in ANKRD11). Moreover, they also found a significant enrichment of eGFR-associated CpGs in regions that bind the transcription factors (TFs), like EBF1, EP300, and CEBPB . Accordingly, DNA methylation in specific CpG sites was associated with eGFR decline and fibrosis in diabetic American Indians .
DNA methylation patterns in specific genes could be relevant as potential biomarkers. The connective tissue growth factor (CTGF or CCN2) is a profibrotic factor, a potential biomarker of renal damage in diabetes, and a potential therapeutic target, as demonstrated in experimental models of renal injury [26, 27]. In diabetic nephropathy (DN), demethylation of the CTGF gene promoter correlates with low eGFR [28, 29]. MTHFR DNA methylation levels were higher in end-stage renal disease (ESRD) patients than in controls and associated with a decreased eGFR . A study carried out in patients with type 1 diabetes (T1D) showed a decrease in IGFBP1 DNA levels from peripheral blood samples compared to normal glucose tolerance subjects, which could be associated with the increased circulating levels of IGFBP-1 in those patients .
Most of the knowledge about DNA methylation on renal damage came from studies in DN. Experimental studies evaluating tubular cells of diabetic mice have found an aberrant DNA hypomethylation in genes involved in glucose metabolism, such as Agt (a marker of renal damage in diabetes) and Hnf4a (a transcription factor regulating transporters for reabsorption). In contrast, other genes were hypermethylated, such as cldn18 . Moreover, increased expression of the pregnane X receptor caused by aberrant demethylation of its promoter was also described , although the biological meaning of these findings remains to be determined. Studies carried out in streptozotocin- (STZ-) induced diabetic mice showed hypomethylation of cldn1-CpG regions and Sirt1 overexpression leading to higher methylation levels of these regions. In parallel with these epigenetic changes, the levels of cldn1 mRNA expression were lower in parietal epithelial cells from diabetic Sirt1 transgenic mice compared to WT cells . Additionally, several studies carried out in whole blood samples from DN patients have identified differentially methylated genes (NRBF2, RUNX3, DAPK3 UNC13B, and DOC2A) associated to different processes such as transcription regulation, inflammation, apoptosis, or exocytosis [35, 36]. In another study, a significant negative correlation between methylation levels of targeted genes (TIMP-2 and AKR1B1) and albuminuria levels was found in early DN .
DNA methylation also participates in the regulation of ECM-related genes. In human kidney samples from CKD patients, differentially methylated regions located in putative enhancers have been described. Genes around these regions include COL IVA 1/2 (a key component of ECM) transforming growth factor beta (TGF-[beta]) and smad proteins, with TGF-[beta]/Smad being a key signalling pathway involved in ECM regulation. In the case of Smad proteins, SMAD3 and SMAD6 cytosine methylation changes were correlated with gene transcription levels . Hyperhomocysteinemia (HHcy) is prevalent in patients with CKD and ESRD and is characterized by an abnormally high level of homocysteine in the blood. In experimental hyperhomocysteinemia-induced renal damage, DNA hypermethylation and upregulation of dnmt1 and dnmt3a were followed by gene expression changes in crucial proteins involved in ECM regulation, including matrix metalloproteinase-9 (MMP-9) (an enzyme that participates in collagen degradation) and downregulation of MMP inhibitors, including tissue inhibitor of metalloproteinase- (TIMP-) 1 and -2. Besides, in injured kidneys there was an imbalance in the methylation status of mmp9 and timps, leading to increased collagen deposition. Importantly, the treatment of these animals with a DNA methylation inhibitor, 5-aza-2-deoxycytidine (5Aza), restored matrix-degrading enzyme MMP-9/TIMP imbalance and ameliorated renal fibrosis . Hypermethylation of the rasal1 gene causes increased Ras-GTPase activity in fibroblasts, leading to proliferation and fibrosis in the kidney . In the experimental model of unilateral ureteral obstruction (UUO), TGF-[beta] induces suppression of Klotho, a known renal antifibrotic protein by hypermethylation of its promoter through induction of dnmt1 and dnmt3a .
DNA methylation can also modulate the inflammatory process in the injured kidney. In dialysis patients, global DNA hypermethylation (total DNA 5-mc) in blood samples was associated with elevated inflammatory markers as ferritin and procalcitonin, the latter being a marker of inflammation due to bacterial infections . In hemodialysis patients, global DNA methylation was higher than in hemodiafiltration patients and DNA methylation is most elevated in inflamed patients . Experimental studies described altered DNA methylation status of a specific CpG within the IFN response element resident in the promoter region of the C3 gene in response to hypoxia and oxidative stress upon ischemia-reperfusion (I/R) injury in rats . In a mouse model of I/R, the analysis of the global level of the DNA hydroxymethylation mark (5-hydroxymethylcytosine (5hmC)) assessed by immunohistochemistry and dot blot showed an apparent decrease in 5hmC levels in ischemic mouse kidney . I/R injury alters the 5hmC levels at specific gene loci at proximal promoter regions of the proinflammatory genes cxcl10 and ifngr2 (non-ligand-binding beta chain of the gamma interferon receptor). This decrease in 5hmC levels is related to an increase in gene expression of cxcl10 and ifngr2. These alterations were associated with dysregulation in TET protein expression, proteins that catalyze the oxidation of 5mC into 5hmC . In systemic sclerosis (SSc), a rare connective tissue disease characterized by chronic inflammation and fibrosis with deleterious effect in the kidney, DNA hypomethylation in [CD4.sup.+] Tlymphocytes from SSc patients decreased the expression of methylation genes such as DNA methyltransferases (DNMT)1 and methyl-CpG-binding domain proteins (MBD)3 and MBD4 [46, 47]. DNA methylation also participates in acute kidney injury (AKI) and renal transplantation. Methylation of the kallikrein promoter has been found in patients with established acute kidney injury (AKI) . Additional, aberrant hypermethylation of the calcitonin gene promoter is more frequent in kidney transplant recipients .
1.1.1. Demethylating Treatments. Together, these studies indicate that monitoring or targeting the epigenome could, therefore, reveal new therapeutic approaches in CKD and open up paths to biomarker discovery and targeted therapy. Demethylating agents could be useful therapeutic approaches. Currently, two demethylating drugs are in clinical use, 5-azacitidine and decitabine, for the treatment of specific forms of myelodysplastic syndrome and acute myeloid leukemia . In an experimental DN model (db/db mouse), treatment with 5-azacitidine or decitabine attenuated the increased expression of dnmtl, markedly diminished albuminuria, and restored podocyte function . Unfortunately, 5-azacitidine and decitabine have significant adverse effects because of their broad demethylating activity and cytotoxicity. Consequently, more specific and less toxic drugs are needed to elucidate the therapeutic potential of these inhibitors.
Another therapeutic experimental approach is the antihypertensive agent hydralazine, used in clinical therapy since the middle of the last century . Hydralazine has been proven to attenuate renal fibrosis in a model of ischemia-reperfusion by inducing expression of hydroxylase TET3, which catalyzes hydroxymethylation and subsequently promotes demethylation of genes such as rasal1 . Other compounds presented demethylating activity, for example, Rhein, a plant-derived anthraquinone which displays strong antifibrotic properties in the experimental model of UUO, probably by reverse Klotho DNA hypermethylation  (Figure 1).
1.2. Histone Modifications and Kidney Diseases. Posttranscriptional histone modifications (PTM) play a critical role in chromatin structure acquiring two configurations, one more closed (heterochromatin) and inactive and another less compact (euchromatin) and associated with active gene transcription. These modifications include acetylation, methylation, ubiquitination, propionylation and crotonylation of lysine residues; methylation, ribosylation and citrullination of arginine residues; and the phosphorylation and glycosylation of serines and threonines . Histone modifications can occur within the folded domain of the histones or in the N- and C-terminal domains that extend beyond the nucleosome [56, 57]. Some of these modifications exert an activating function (such as H3K4me3, AcH3, AcH4, and AcH3K9) facilitating the opening of the chromatin and the union of the transcriptional machinery, while other modifications are repressive (such as H3K27me3, H3K9me2/3, and H4K20me3,), allowing the compaction of chromatin and preventing the union of the transcriptional machinery (Figure 1).
The adding or removing of histone marks is carried out by a group of enzymes named (1) "writers," responsible for adding ("writing") different epigenetic marks such as HAT (histone acetyltransferase), which adds acetyl groups to histone tails, (2) "erasers," responsible for the removal of epigenetic marks of the histone, such as histone deacetylases (HDACs) or histone demethylases (HDMs), and (3) "readers," whose function is to recognize the different epigenetic marks added in the histones. Among the reader proteins, one of the most relevant are the BET proteins, which contain bromodomains that recognize acetylated lysine residues in the histone tails [55, 58]. Next, we will discuss how these enzymes and epigenetic modifications could participate in renal pathology.
1.2.1. Histone Acetylation. Histone acetylation reduces the net positive charge of histones and weakens interactions with DNA. This perturbation in chromatin facilitates DNA transcription. The acetylation process occurs when the acetyl group (COCH3) is transferred from acetyl-coenzyme A (acetyl-CoA) to lysine residues, by a process regulated by histone acetyltransferases (HATs) . By contrast, the acetylated residues can be recovered by three classes of histone deacetylases (HDAC): class I HDACs which are zinc-dependent and located in the nucleus, class II HDACs which are also zinc-dependent but are present in the nucleus and cytoplasm, and class III HDACs called sirtuins (Sirt 1-7) which depend upon NAD+ for their activity and are present in the nucleus, cytoplasm, and mitochondria .
Many studies have found that histone acetylation participates in experimental renal fibrosis (Figure 2). Studies done in the unilateral ureteral obstruction (UUO) model have shown that treatment with various HDAC inhibitors, such as trichostatin A or the selective class I HDAC inhibitor MS-275, reduced renal fibrosis by diminishing profibrotic markers (a-smooth muscle actin (SMA)) and accumulation of ECM proteins, including fibronectin and type I collagen [60-63]. In these studies, the most relevant downstream fibrotic-related mechanisms were inhibited by HDAC inhibition, including TGF-[beta]/Smad, EGFR, and STAT3 signalling pathways  or JNK-dependent Notch-2 signalling pathways [61-63]. In experimental diabetes induced by streptozotocin injection in mice, HDAC inhibition with trichostatin A diminished profibrotic gene overexpression. Moreover, in vitro studies in rat tubular epithelial cells (NRK52-E cell line) showed that HDAC inhibition by the HDAC inhibitor Trichostatin A (TSA), valproic acid, SK7041, or N-acetylcysteine or gene silencing of HDAC-1/2 restored TGF-[beta]1-induced phenotypic changes, including induction of [micro]-SMA and loss of epithelial markers , suggesting that histone acetylation could also be involved in renal fibrosis by modulating the epithelial phenotype.
HDAC inhibitors have also been involved in the regulation of renal inflammation (Figure 2). In a model of lupus nephritis, the HDAC inhibitor ITF2357 diminished the proinflammatory gene expression of il6, il-1[beta], and the systemic lupus erythematosus (SLE) serum biomarker IgG2a . In Adriamycin-induced renal fibrosis, two HDAC inhibitors, TSA and valproic acid, reduced the expression of the chemokines mcp1 and mip1[beta] and diminished renal macrophage infiltration . Similar effects of both HDAC inhibitors were described in the UUO model by reduction of CSF-1 in renal tubule interstitial space, a chemokine known to be involved in macrophage infiltration . Moreover, TSA also decreased juxtaglomerular hyperplasia in damaged kidneys and the degree of fibrosis analyzed by protein levels of fibronectin and collagen I. On the other hand, TSA reduced the percentage of FOXP3+IL-17+ cells and the genic expression of foxp3 and roryt, key transcription factors involved in the modulation of Th17 differentiation .
Histone acetylation can also contribute to the inflammatory process associated with diabetes (Figure 2). In blood monocytes of diabetic patients, the acetylation of histones H3K9/14Ac and H4K5,8,12Ac in promoters of inflammatory genes such as TNF-[alpha] and COX-2 was increased . In models of acute kidney injury, TSA also exerts anti-inflammatory actions, including reduction in cytokine and chemokine expression through an increase of the anti-inflammatory protein microglia/macrophage WAP domain protein  and a decrease in NF-[kappa]B signalling .
There are now some ongoing clinical trials studying the effect of different HDAC inhibitors, such as belinostat, entinostat, vorinostat, and panobinostat, in renal tumors [70-72]. Previous studies in other types of tumors, including lymphoma and myeloma, have shown beneficial effects, whereas these drugs do not have enough effective activity in the treatment of renal tumors [73-75]. Thus, these data indicated that future research with epigenetic modulators in renal cancer patients would be necessary.
1.2.2. Role of BET Proteins in Protein Acetylation. The family of bromodomain and extraterminal (BET) proteins is composed of four members: BRD2, BRD3, BRD4 (ubiquitously expressed), and BRDT. BET proteins contain a tandem of two conserved N-terminal bromodomains (BD1 and BD2) and an extraterminal domain. BD interacts with acetylated lysine residues in histones acting as an epigenetic "reader" . Studies on the cancer field have described that BRD4 contributes to the recruitment of the positive transcription elongation factor b (P-TEFb) complex (heterodimer of CDK9 and cyclin T1, T2, or K) to the promoter region and activates RNA polymerase II-dependent (RNAPII) transcription. BRD4 binds to acetylated histones in the enhancer or promoter regions of oncogenes and inflammatory genes and by this mechanism participates in malignancies and inflammatory diseases . Intensive pharmacological research has focused on the design of BET protein inhibitors (iBETs). One of the earliest developed and best studied is JQ1. This iBET was developed by Jun Qi, a researcher belonging to Chris French's group , who demonstrated that JQ1 competes for the bromodomain-binding pocket and displaces BET proteins from the binding to acetylated lysine residues located in histones. This interrupts the remodelling of chromatin and prevents the expression of certain genes . First studies were done in experimental proliferative pathologies, including midline carcinoma and hematological malignances, showing that JQ1 regulates cell proliferation and apoptosis, by reducing the expression of cancer-promoting genes, such as c-Myc and bcl-2, two target genes of BRD4 , but now, many preclinical studies have shown its beneficial effects in different pathologies. In a murine model of polycystic kidney disease, iBET JQ1 delayed cyst growth and preserved renal function, by inhibiting c-Myc gene and cystic epithelial cell proliferation . Many in vitro studies have described that iBETs could exert anti-inflammatory actions, by inhibiting proinflammatory gene expression [81-83]. Our group had recently described that in cultured tubular epithelial cells stimulated with TNF-[alpha], treatment with JQ1 decreased the expression of several genes associated with inflammatory processes and immune response . Moreover, in different models of renal damage (UUO, immunemediated glomerulonephritis, and angiotensin II-induced renal damage), we showed that JQ1 treatment inhibited renal inflammation . By chromatin immunoprecipitation experiments, we described that the mechanism involved in the anti-inflammatory actions of JQ1 is mediated by the displacement of BRD4 binding to acetylated histone H3 in the promoter region of several proinflammatory genes (such as IL-6, CCL-2, and CCL-5) (Figure 3). Additionally, the role of BRD4 on the regulation of proinflammatory genes was demonstrated by gene silencing . Some preclinical studies have confirmed this anti-inflammatory mechanism of iBETs in other experimental pathologies [85, 86].
BET proteins can also bind to acetylated residues in other proteins besides histones, including transcription factors, regulating gene transcription. In an experimental diabetic model of renal damage in db/db mice, increased acetylation of transcription factors NF-[kappa]B and STAT3 were found, showing that modulation of these signalling pathways could be an important mechanism involved in renal inflammation . Many experimental studies have found that blockade of the NF-[kappa]B pathway using specific inhibitors of this pathway, or indirectly by drugs used in the clinic to treat CKD patients, including blockers of the renin angiotensin system, attenuates renal inflammation and ameliorates disease progression [88, 89]. The RelA NF-[kappa]B subunit is activated by acetylation of lysine 310. Intensive research in the cancer field has unraveled the role of BET proteins in NF-[kappa]B pathway regulation, demonstrating that BRD4 binding to acetylated lysine-310 of RelA is essential for recruiting BRD4 and CDK9 to the promoters of specific NF-[kappa]B target genes [90-93]. We have described that JQ1 reduced RelA nuclear levels in several models of renal damage and in cultured cells in a proinflammatory environment and thereby blocked NF-[kappa]B transcriptional activation and downregulated severalNF-[kappa]B-controlled genes, including mcpl and ill7a , suggesting another mechanism contributing to the anti-inflammatory effects of JQ1 in renal damage. This mechanism has been confirmed with other iBETs , associated with inhibition of renal infiltration of macrophages (Figure 3).
Studies blocking Th17 immune response by different approaches, including neutralizing antibodies against IL17A, soluble receptor, ROR[gamma]t inhibitors, or genetically modified mice, have demonstrated the involvement of this immune response in chronic inflammatory diseases, including immune and nonimmune experimental renal damage [95-102]. BET proteins have been involved in the differentiation of naive CD4 T lymphocytes into Th17 cells . In two models of experimental renal damage, UUO, and immune-mediated glomerulonephritis, we have found that JQ1 treatment markedly diminished the presence of IL17A-expressing cells and the renal levels of IL-17A and other Th17-related cytokines, such as ccl20 and csfl . Other studies in different pathologies support these data, as described in collagen-induced arthritis and experimental autoimmune encephalomyelitis [104, 105]. BET proteins can modulate Th17 response by a direct effect on il17a gene expression. BRD4 and BRD2 bind to the regulatory region of CNS2 that controls IL-17A transcription . Moreover, p300, a transcriptional coactivator that possesses bromodominium and acetylase activity, binds to the promoter of the il17a gene in murine Th17 cells, facilitating accessibility to chromatin . In summary, these data expand the neutralization strategies of inflammatory effects mediated by IL-17A in the kidney using iBETs.
Several evidences suggest that iBETs can also present antifibrotic properties, as described in pulmonary fibrosis , liver , and cardiac damage . The in vitro experiments carried out in tubular epithelial cells stimulated with TGF-[beta]1 showed that the inhibition of BRD4 functions by silencing their gene or treatment with JQ1 leads to a decrease in the expression of fibrotic genes, such as [micro]-smooth muscle actin and fibronectin . In the UUO model, treatment with I-BET151 decreased ECM protein levels and the activation of renal fibroblasts . Recent studies confirm the beneficial effect of JQ1 in fibrosis and inflammation consequent to the radiation used in radiotherapy in thoracic cancer, by suppressing BRD4, c-MYC, collagen I, TGF-[beta], p65, p-SMAD2, and p-SMAD3 after irradiation .
Different pharmacological companies have developed several iBETs; some of them are now being used in clinical trials. Most of them have been used in different types of cancer, such as breast cancer, small cell lung cancer, or prostate cancer. For example, ABBV-075 presents a potential antineoplastic activity, leading to an inhibition of cell growth in certain tumors . TEN-010, from Roche, is tested in patients with acute myeloid leukemia . RVX000222, of Resverlogix, was evaluated in patients with diabetes mellitus type 2 and with cardiovascular diseases of high risk . Future studies in renal diseases are required.
1.2.3. Histone Methylation. The process of histone methylation is related to the capacity to transfer one, two, or three methyl groups (CH3) from the S-adenosyl-L-methionine cofactor to lysine or arginine residues in the histone, generating mono-, di-, or trimethyl lysine/arginine residues. This process is developed by a group of enzymes named histone methyltransferases (HMTs) . Some methylation in specific lysine modifications exerts an activating function (H3K4me3) facilitating the opening of the chromatin and the union of the transcriptional machinery, while other modifications are repressive (H3K27me3, H3K9me2/ 3, and H4K20me3,), allowing the compaction of chromatin and avoiding the binding of the transcriptional machinery .
Epigenetic modulation through PTMs such as histone methylation can contribute to renal fibrosis (Figure 1). In the experimental UUO model in mice, H3K9me3 methylation was increased mainly in proximal tubules and myofibroblasts of obstructed kidneys. In the same study, in vitro analysis done in primary rat renal fibroblasts and proximal tubule cells (NRK-52e), TGF-[beta] stimulation increased H3K9me3 associated to induction of a-SMA expression . In rat mesangial cells, TGF-[beta] increased profibrotic genes such as Col1a1 and PAI-1, associated to increased H3K4me mark levels . A study developed in a podocyte-specific PTIP (a component of an H3K4 methyltransferase complex) knockout mice showed a reduction in H3K4me associated with disease phenotype .
Recent studies indicate that H3K4me1/2/3 is essential for the deregulation of key genes in the pathogenesis of DN . In this sense, modifications such as H3K4me and H3K9me1 (associated with promoters of proinflammatory genes) activated the expression of these genes in hyperglycemic conditions . Moreover, RelA NF-[kappa]B activation was observed in endothelial cells in high-glucose conditions associated with an increase of H3K4me1 in the p65 promoter region [118, 119]. Accordingly, in an animal model of nephrectomy in db/db mice, increased H3K4me2 renal levels were associated with renal function loss and glomerulosclerosis, and this effect was diminished by treatment with MCP-1/CCL2 antagonist (Spiegelmer mNOX-E36) . In an ischemia-reperfusion injury model, the induction of proinflammatory genes such as TNF-[alpha] and MCP-1 was related to changes in histone profiles along these genes as H3K4m3 or modification in histone-modifying enzymes (Set1 and BRG1) [121, 122].
1.2.4. Histone Phosphorylation. Phosphorylation occurs predominantly on serine, threonine, and tyrosine side chains or residues through a phosphoester bond formation; this constitutes approximately 86.4%, 11.8%, and 1.8%, respectively, of the human phosphor-proteome . Also, this phosphorylation can occur in less percentage in histidine, lysine, and arginine through phosphoramidate bonds. Histone H2AX phosphorylation ([gamma]H2AX) at ser139 was induced by ataxia telangiectasia-mutated (ATM) protein kinase, and is a key marker of DNA damage because is accumulated in DNA to recruit DNA repair complex [124, 125].
Previous studies described the role of [gamma]H2AX in oxidative stress . In an I/R renal injury model in mice, injured kidneys presented elevated levels of [gamma]H2AX mainly located in tubular epithelial cells . Other studies developed in a model of diabetic nephropathy induced by STZ in Nox1deficient mice showed lower levels of [gamma]H2AX in glomerular and tubular extracts in these KO mice compared to elevated levels in diabetic mice, suggesting the possible role of oxidative stress . These results demonstrated the new role of histone phosphorylation in the pathological process that constitutes renal damage (Figure 1).
1.2.5. Histone Crotonylation. Histone crotonylation is a new posttranscriptional histone modification in lysine residues (Kcr). Crotonate is a short-chain unsaturated carboxylic acid (C[H.sub.3]CH=CHC[O.sub.2]H) that increases the crotonylation in histones. The original structure and different localization of this histone modification established an apparent variation compared to lysine acetylation (Kac) [129, 130]. This type of modification has the function of activating promoters or potential enhancers. Moreover, histone crotonylation is increased in sex chromosomes and marks testis-specific genes . A recent study established the presence of histone crotonylation in kidney damage after AKI using a mouse model induced by folic acid administration . PGC-1 is a transcription factor governing gene expression of mitochondrial biogenesis and function, with a protective role in renal diseases . Enrichment of histone crotonylation at the pgc1 gene was found in response to inflammatory cytokines such as TWEAK in tubular cells and in AKI kidney tissue . Crotonate administration to folic acid-injected mice during 48 hours increased renal pgc1[alpha] and sirt3 mRNA and decreased ccl2 mRNA expression indicating that crotonate protects from experimental AKI (Figure 1) .
1.3. miRNAs and Kidney Diseases. miRNAs are a class of endogenous single-stranded noncoding RNAs with a size within 21-25 nucleotides. miRNAs are involved in posttranscriptional regulation of gene expression by binding to the 3 -untranslated regions -untranslated regions (5 -UTRs) of the target mRNAs and modulating its degradation [133-137]. These noncoding RNAs are considered as epigenetic modulators due to their capacity of modulating gene expression (Figure 1) .
The miRNA levels have been investigated in patients with CKD to elucidate their potential role as biomarkers in CKD progression. A study carried out in a focal segmental glomerulosclerosis (FSG) patient cohort showed increased levels of miR-196a in urine of patients, relating this miRNA with proteinuria and interstitial fibrosis . Furthermore, studies performed in podocytes of FSG patients showed decreased levels of miRNAs that belong to miR-30 related to a protective role of the inhibition of Notch1 and p53 pathways, molecules involved in podocyte injury [139, 140]. Studies carried out in proximal tubular epithelial cells and mesangial cells showed that miRNAs belonging to the let-7 miRNA family are positive regulators of renal fibrosis due to their capacity to upregulate the TGF-[beta]1 receptor, increasing the inflammatory TGF-[beta]1 pathway [141, 142]. miR-21 has also shown a profibrotic effect diminishing PPAR[micro] levels and, consequently, lipid oxidation pathways in wild-type mice in response to kidney injury . In contrast, the miR-29 family has shown antifibrotic effects. In a STZ-induced diabetic model developed in miR-29a transgenic mice, miR29a reduced glomerular fibrosis and inflammation; these results were confirmed in miR-29 knockdown mice that showed an increase in histone deacetylase activity inducing renal dysfunction through podocyte apoptosis and proteinuria [144, 145]. Furthermore, in the UUO model, miR-29 ultrasound-microbubble-mediated gene transfer reduced renal fibrosis . Another antifibrotic miRNA elucidated in plasma of CKD patients was miR-16 .
miRNA-146b-5p has a protective role in reducing IL-6 and IL-8 levels in glomerular mesangial cells . miRNA-663a and miRNA-423-5p have been related with the NF-[kappa]B signalling pathway, an important target in the development of lupus nephritis (LN) . Moreover, miR3201 and miR-1273a are downregulated and associated with endocapillary glomerular inflammation in LN patients . Interestingly, miR-223-3p and miR-93-5p are associated with IL-6 levels in stage 4 CKD patients, while in stage 5 CKD patients these miRNAs have been related with eGFR .
The role of miRNAs in AKI has been also investigated, although its contribution to the disease is not well understood. A study carried out in an experimental model of cisplatin-induced AKI in mice showed an antifibrotic role of miR-122 inhibiting FOXO3 translocation and, therefore, reducing inflammatory cell infiltration and increasing cell viability and fibrosis. In the same study, miR-34 was described as profibrotic miRNA since it is involucrate in upregulating foxo3 levels . miR-146a is also related to the inflammatory process in AKI. This miRNA is upregulated in inflammation states through IL-1/TLR activation of NF-[kappa]B in cultured renal proximal tubular cells . Other miRNAs have been found to be downregulated in AKI and proposed as protective miRNAs such as miR-17-92, whose overexpression ameliorates I/R injury effects on kidney cells . Additional investigations discovered upregulated miRNAs such as miR-20a, miR-192, miR-187, miR-805, and miR-194 in kidneys of C57BL/6 mice with I/R injury .
Different miRNAs have been associated with DN development. miR-192 has been shown to be increased in renal biopsies of diabetic nephropathy patients  related to fibrosis and a decreased glomerular filtration rate . miR-192 is upregulated by TGF-[beta], triggered by the increase in glucose levels, and is involucrated in TGF-[beta]-induced collagen expression. Other miRNAs have been related to TGF[beta]/glucose increased levels. In a UUO model and tubular epithelial cells, it has been observed that miR-21 is upregulated by elevated TGF-[beta]/glucose levels [158-160]. In the same way, miR-214 and miR-21 expressions were upregulated due to TGF-[beta] increased levels and induced EMT in rat tubular epithelial cells (NRK52E) .
In contrast, high-glucose levels downregulate miR-29a expression in HK2 cells, negatively regulating collagen IV expression . miRNA regulation of the inflammatory process in DN patients is still unclear. miR-146a seems to be protective against DN inflammation in an STZ-induced diabetes model in miR-146a (-/-) mice, increasing renal macrophage infiltration and upregulation of proinflammatory genes such as IL-1[beta] and IL-18 . Consequently, with the miR-29a effects in fibrosis, Chen et al.  reported in type 2 diabetes in db/db mice anti-inflammatory and antifibrotic functions of miR-29b, with results associated with NF-KB-driven renal inflammation and T-bet/Th1-mediated immune response. In contrast, Guo et al.  demonstrated a miR-29c proinflammatory effect in DN carried out by tri-stetraprolin (TTP), targeting DN patients and immortalized mouse podocytes (MPC5).
In any case, a recent review about miRNA in patients with diabetic kidney disease identified miR-21-5p, miR29a-3p, miR-126-3p, miR-192-5p, miR-214-3p, and miR342-3p that are consistently dysregulated among different studies, and bioinformatics analysis revealed that all of them play essential roles in diabetic kidney disease. Finally, a recent meta-analysis from 20 datasets from human and animal studies is aimed at recognizing consistently dysregulated miRNAs in renal fibrosis and identifying 5 upregulated and 2 downregulated miRNA . Thus, miR-1423p, miR-2233p, miR-215p, miR-1425p, and miR-2143p were shown to be consistently upregulated in several reports, whereas miR-29c-3p and miR-200a-3p were downregulated. However, the inclusion of different etiologies, together with the mixture of human and animal samples, can hinder to obtain conclusive results.
Common mechanisms involved in CKD, including oxidative stress, inflammation, and uremic toxins, can contribute to the renal damage progression by inducing epigenetic modifications, as we have reviewed here. One crucial clinical unmet is the lack of effective CKD treatment, with epigenetic drugs being a source of potential and novel therapeutic options due to the dynamic nature and reversibility of epigenetic modifications. Many preclinical studies are using demethylating agents, HDAC inhibitors, or BET protein inhibitors in experimental renal diseases with successful results. On the other hand, clinical studies have also been developed in patients. HDAC inhibitors such as belinostat, entinostat, vorinostat, and panobinostat and BET protein inhibitors, such as ABBV-075 or TEN-010, have been tested in patients with several tumors, such as lymphoma and myeloma, with beneficial effects whereas these compounds do not have enough effective activity in the treatment of renal tumors. Other IBET RVX000222 has been used with good results in patients with diabetes mellitus type 2 and cardiovascular diseases closely related with CKD. However, future studies in renal diseases are required to gain insight into epigenetic mechanisms associated with the development of renal disease. Body fluids are an accessible source for epigenetic biomarkers. DNA methylation and miRNAs have been studied in patients as biomarkers in CKD progression, e.g., diabetic nephropathy and focal segmental glomerulosclerosis, respectively. All of these epigenetic modifications are a novel field of study to find new targets that can be used as therapeutic approaches and treatments in the diagnostic of CKD and in the monitoring of the progression of renal disease.
In addition, considering the high susceptibility of the genome to epigenetic changes mediated by environmental factors during fetal development, it is of pivotal importance to determine whether the maternal environment can condition epigenetic changes in the fetus associated with the development of renal pathologies during adulthood, generating an important tool for the early detection and prevention of kidney diseases.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Jose Luis Morgado-Pascual and Vanessa Marchant contributed equally to this work.
This work was supported by Instituto de Salud Carlos III and Fondos FEDER European Union (PI14/00041, PI15/00960, PI16/01354, PI17/00119, and PI17/01244), Red de Investigation Renal (REDinREN; RD16/0009), Comunidad de Madrid (B2017/BMD-3751 NOVELREN-CM), Fondecyt 1181574 (BK), Sociedad Espanola de Nefrologia, and the "Juan de la Cierva Formacion" training program of the Ministerio de Economia, Industria y Competitividad which supported the salary of S.R-M (FJCI-2016-29050). V. Marchant has a CONICYT Scholarship for his graduate studies at the PhD program in Medical Science, Universidad Austral de Chile. The Centro de Estudios Cientificos is funded by the Chilean Government through the Centers of Excellence Basal Financing Program of CONICYT.
 C. H. Waddington, "The epigenotype," Endeavour, vol. 1, pp. 18-20, 1942.
 C. H. Waddington, "Canalization of development and genetic assimilation of acquired characters," Nature, vol. 183, no. 4676, pp. 1654-1655, 1959.
 C. H. Waddington, "The epigenotype," International Journal of Epidemiology, vol. 41, no. 1, pp. 10-13, 2012.
 A. D. Goldberg, C. D. Allis, and E. Bernstein, "Epigenetics: a landscape takes shape," Cell, vol. 128, no. 4, pp. 635-638, 2007.
 N. Wanner and W. Bechtel-Walz, "Epigenetics of kidney disease," Cell and Tissue Research, vol. 369, no. 1, pp. 75-92, 2017.
 S. T. Keating and A. El-Osta, "Glycemic memories and the epigenetic component of diabetic nephropathy," Current Diabetes Reports, vol. 13, no. 4, pp. 574-581, 2013.
 P. Beckerman, Y. A. Ko, and K. Susztak, "Epigenetics: a new way to look at kidney diseases," Nephrology, Dialysis, Transplantation, vol. 29, no. 10, pp. 1821-1827, 2014.
 M. M. Suzuki and A. Bird, "DNA methylation landscapes: provocative insights from epigenomics," Nature Reviews. Genetics, vol. 9, no. 6, pp. 465-476, 2008.
 D. N. Cooper, "Eukaryotic DNA methylation," Human Genetics, vol. 64, no. 4, pp. 315-333, 1983.
 M. Ehrlich, M. A. Gama-Sosa, L. H. Huang et al., "Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells," Nucleic Acids Research, vol. 10, no. 8, pp. 2709-2721, 1982.
 A. Razin and A. D. Riggs, "DNA methylation and gene function," Science, vol. 210, no. 4470, pp. 604-610, 1980.
 A. Razin, "CpG methylation, chromatin structure and gene silencing-a three-way connection," The EMBO Journal, vol. 17, no. 17, pp. 4905-4908, 1998.
 S. Pradhan, A. Bacolla, R. D. Wells, and R. J. Roberts, "Recombinant human DNA (cytosine-5) methyltransferase. I. Expression, purification, and comparison of de novo and maintenance methylation," The Journal of Biological Chemistry, vol. 274, no. 46, pp. 33002-33010, 1999.
 M. Okano, S. Xie, and E. Li, "Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases," Nature Genetics, vol. 19, no. 3, pp. 219-220, 1998.
 C. L. Hsieh, "In vivo activity of murine de novo methyltransferases, Dnmt3a and Dnmt3b," Molecular and Cellular Biology, vol. 19, no. 12, pp. 8211-8218, 1999.
 M. Ko, J. An, W. A. Pastor, S. B. Koralov, K. Rajewsky, and A. Rao, "TET proteins and 5-methylcytosine oxidation in hematological cancers," Immunological Reviews, vol. 263, no. 1, pp. 6-21, 2015.
 D. M. Marzese and D. S. B. Hoon, "Emerging technologies for studying DNA methylation for the molecular diagnosis of cancer," Expert Review of Molecular Diagnostics, vol. 15, no. 5, pp. 647-664, 2015.
 A. Nebbioso, F. P. Tambaro, C. Dell'Aversana, and L. Altucci, "Cancer epigenetics: moving forward," PLoS Genetics, vol. 14, no. 6, article e1007362, 2018.
 P. Kaushik and J. T. Anderson, "Obesity: epigenetic aspects," Biomolecular Concepts, vol. 7, no. 3, pp. 145-155, 2016.
 C. Ling and T. Ronn, "Epigenetic markers to further understand insulin resistance," Diabetologia, vol. 59, no. 11, pp. 2295-2297, 2016.
 E. Loche and S. E. Ozanne, "Early nutrition, epigenetics, and cardiovascular disease," Current Opinion in Lipidology, vol. 27, no. 5, pp. 449-458, 2016.
 L. J. Smyth, G. J. McKay, A. P. Maxwell, and A. J. McKnight, "DNA hypermethylation and DNA hypomethylation is present at different loci in chronic kidney disease," Epigenetics, vol. 9, no. 3, pp. 366-376, 2014.
 M. R. Wing, J. M. Devaney, M. M. Joffe et al., "DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC study," Nephrology, Dialysis, Transplantation, vol. 29, no. 4, pp. 864-872, 2014.
 A. Y. Chu, A. Tin, P. Schlosser et al., "Epigenome-wide association studies identify DNA methylation associated with kidney function," Nature Communications, vol. 8, no. 1, p. 1286, 2017.
 C. Qiu, R. L. Hanson, G. Fufaa et al., "Cytosine methylation predicts renal function decline in American Indians," Kidney International, vol. 93, no. 6, pp. 1417-1431, 2018.
 E. Sanchez-Lopez, R. Rodrigues Diez, J. Rodriguez Vita et al., "Connective tissue growth factor (CTGF): a key factor in the onset and progression of kidney damage," Nefrologia, vol. 29, no. 5, pp. 382-391, 2009.
 S. Rayego-Mateos, R. Rodrigues-Diez, J. L. Morgado-Pascual et al., "Connective tissue growth factor is a new ligand of epidermal growth factor receptor," Journal of Molecular Cell Biology, vol. 5, no. 5, pp. 323-335, 2013.
 B. Yi, H. Zhang, H. Zhou, X. Cai, J. Sun, and Y. Liu, "High glucose induce the demethylation of CTGF promoter and gene expression," Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi, vol. 27, article 74750, 2011.
 H. Zhang, X. Cai, B. Yi, J. Huang, J. Wang, and J. Sun, "Correlation of CTGF gene promoter methylation with CTGF expression in type 2 diabetes mellitus with or without nephropathy," Molecular Medicine Reports, vol. 9, no. 6, pp. 2138-2144, 2014.
 M. Ghattas, F. El-Shaarawy, N. Mesbah, and D. Abo-Elmatty, "DNA methylation status of the methylenetetrahydrofolate reductase gene promoter in peripheral blood of end-stage renal disease patients," Molecular Biology Reports, vol. 41, no. 2, pp. 683-688, 2014.
 T. Gu, H. Falhammar, H. F. Gu, and K. Brismar, "Epigenetic analyses of the insulin-like growth factor binding protein 1 gene in type 1 diabetes and diabetic nephropathy," Clinical Epigenetics, vol. 6, no. 1, p. 10, 2014.
 T. Marumo, S. Yagi, W. Kawarazaki et al., "Diabetes induces aberrant DNA methylation in the proximal tubules of the kidney," Journal of the American Society of Nephrology, vol. 26, no. 10, pp. 2388-2397, 2015.
 A. Watanabe, T. Marumo, W. Kawarazaki et al., "Aberrant DNA methylation of pregnane X receptor underlies metabolic gene alterations in the diabetic kidney," American Journal of Physiology. Renal Physiology, vol. 314, no. 4, pp. F551-F560, 2018.
 K. Hasegawa, S. Wakino, P. Simic et al., "Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes," Nature Medicine, vol. 19, no. 11, pp. 1496-1504, 2013.
 C. Sapienza, J. Lee, J. Powell et al., "DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy," Epigenetics, vol. 6, no. 1, pp. 20-28, 2011.
 C. G. Bell, A. E. Teschendorf, V. K. Rakyan, A. P. Maxwell, S. Beck, and D. A. Savage, "Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus," BMC Medical Genomics, vol. 3, no. 1, p. 33, 2010.
 O. Aldemir, F. Turgut, and C. Gokce, "The association between methylation levels of targeted genes and albuminuria in patients with early diabetic kidney disease," Renal Failure, vol. 39, no. 1, pp. 597-601, 2017.
 Y. A. Ko, D. Mohtat, M. Suzuki et al., "Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development," Genome Biology, vol. 14, no. 10, article R108, 2013.
 S. Pushpakumar, S. Kundu, N. Narayanan, and U. Sen, "DNA hypermethylation in hyperhomocysteinemia contributes to abnormal extracellular matrix metabolism in the kidney," The FASEB Journal, vol. 29, no. 11, pp. 4713-4725, 2015.
 W. Bechtel, S. McGoohan, E. M. Zeisberg et al., "Methylation determines fibroblast activation and fibrogenesis in the kidney," Nature Medicine, vol. 16, no. 5, pp. 544-550, 2010.
 S. Yin, Q. Zhang, J. Yang et al., "TGF[beta]-incurred epigenetic aberrations of miRNA and DNA methyltransferase suppress klotho and potentiate renal fibrosis," Biochimica et Biophysica Acta (BBA)--Molecular Cell Research, vol. 1864, no. 7, pp. 1207-1216, 2017.
 S. Kato, B. Lindholm, P. Stenvinkel et al., "DNA hypermethylation and inflammatory markers in incident Japanese dialysis patients," Nephron Extra, vol. 2, no. 1, pp. 159-168, 2012.
 A. B. Ghigolea, R. A. Moldovan, and M. Gherman-Caprioara, "DNA methylation: hemodialysis versus hemodiafiltration," Therapeutic Apheresis and Dialysis, vol. 19, no. 2, pp. 119-124, 2015.
 J. R. Pratt, M. D. Parker, L. J. Affleck et al., "Ischemic epigenetics and the transplanted kidney," Transplantation Proceedings, vol. 38, no. 10, pp. 3344-3346, 2006.
 N. Huang, L. Tan, Z. Xue, J. Cang, and H. Wang, "Reduction of DNA hydroxymethylation in the mouse kidney insulted by ischemia reperfusion," Biochemical and Biophysical Research Communications, vol. 422, no. 4, pp. 697-702, 2012.
 G. Murdaca, M. Contatore, R. Gulli, P. Mandich, and F. Puppo, "Genetic factors and systemic sclerosis," Autoimmunity Reviews, vol. 15, no. 5, pp. 427-432, 2016.
 W. Lei, Y. Luo, W. Lei et al., "Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis," Scandinavian Journal of Rheumatology, vol. 38, no. 5, pp. 369-374, 2009.
 S. W. Kang, P. A. B. Shih, R. O. Mathew et al., "Renal kallikrein excretion and epigenetics in human acute kidney injury: expression, mechanisms and consequences," BMC Nephrology, vol. 12, no. 1, p. 27, 2011.
 T. K. Mehta, M. O. Hoque, R. Ugarte et al., "Quantitative detection of promoter hypermethylation as a biomarker of acute kidney injury during transplantation," Transplantation Proceedings, vol. 38, no. 10, pp. 3420-3426, 2006.
 E. J. B. Derissen, J. H. Beijnen, and J. H. M. Schellens, "Concise drug review: azacitidine and decitabine," The Oncologist, vol. 18, no. 5, pp. 619-624, 2013.
 L. Zhang, Q. Zhang, S. Liu et al., "DNA methyltransferase 1 may be a therapy target for attenuating diabetic nephropathy and podocyte injury," Kidney International, vol. 92, no. 1, pp. 140-153, 2017.
 E. M. Berg and M. Zeisberg, "A rationale for epigenetic repurposing of hydralazine in chronic heart and kidney failure," Journal of Clinical Epigenetics, vol. 2, no. 1, p. 3, 2016.
 B. Tampe, U. Steinle, D. Tampe et al., "Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression," Kidney International, vol. 91, no. 1, pp. 157-176, 2017.
 Q. Zhang, S. Yin, L. Liu, Z. Liu, and W. Cao, "Rhein reversal of DNA hypermethylation-associated klotho suppression ameliorates renal fibrosis in mice," Scientific Reports, vol. 6, no. 1, p. 34597, 2016.
 G. Zhang and S. Pradhan, "Mammalian epigenetic mechanisms," IUBMB Life, vol. 66, no. 4, pp. 240-256, 2014.
 P. Tessarz and T. Kouzarides, "Histone core modifications regulating nucleosome structure and dynamics," Nature Reviews. Molecular Cell Biology, vol. 15, no. 11, pp. 703-708, 2014.
 G. E. Zentner and S. Henikoff, "Regulation of nucleosome dynamics by histone modifications," Nature Structural & Molecular Biology, vol. 20, no. 3, pp. 259-266, 2013.
 T. Jenuwein and C. D. Allis, "Translating the histone code," Science, vol. 293, no. 5532, pp. 1074-1080, 2001.
 S. Ramakrishnan and R. Pili, "Histone deacetylase inhibitors and epigenetic modifications as a novel strategy in renal cell carcinoma," The Cancer Journal, vol. 19, no. 4, pp. 333-340, 2013.
 N. Liu, S. He, L. Ma et al., "Blocking the class I histone deacetylase ameliorates renal fibrosis and inhibits renal fibroblast activation via modulating TGF-beta and EGFR signaling," PLoS One, vol. 8, no. 1, article e54001, 2013.
 T. Marumo, K. Hishikawa, M. Yoshikawa, J. Hirahashi, S. Kawachi, and T. Fujita, "Histone deacetylase modulates the proinflammatory and -fibrotic changes in tubulointerstitial injury," American Journal of Physiology. Renal Physiology, vol. 298, no. 1, pp. F133-F141, 2010.
 C.-W. Tung, Y.-C. Hsu, C.-J. Cai et al., "Trichostatin A ameliorates renal tubulointerstitial fibrosis through modulation of the JNK-dependent Notch-2 signaling pathway," Scientific Reports, vol. 7, no. 1, article 14495, 2017.
 W. P. Wu, Y. G. Tsai, T. Y. Lin, M. J. Wu, and C. Y. Lin, "The attenuation of renal fibrosis by histone deacetylase inhibitors is associated with the plasticity of FOXP3+IL-[17.sup.+] T cells," BMC Nephrology, vol. 18, no. 1, p. 225, 2017.
 H. Noh, E. Y. Oh, J. Y. Seo et al., "Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-[beta]1-induced renal injury," American Journal of Physiology. Renal Physiology, vol. 297, no. 3, pp. F729-F739, 2009.
 N. L. Regna, C. B. Chafin, S. E. Hammond, A. G. Puthiyaveetil, D. L. Caudell, and C. M. Reilly, "Class I and II histone deacetylase inhibition by ITF2357 reduces SLE pathogenesis in vivo," Clinical Immunology, vol. 151, no. 1, pp. 29-42,
 K. Van Beneden, C. Geers, M. Pauwels et al., "Comparison of trichostatin a and valproic acid treatment regimens in a mouse model of kidney fibrosis," Toxicology and Applied Pharmacology, vol. 271, no. 2, pp. 276-284, 2013.
 F. Miao, I. G. Gonzalo, L. Lanting, and R. Natarajan, "In vivo chromatin remodeling events leading to inflammatory gene transcription under diabetic conditions," The Journal of Biological Chemistry, vol. 279, no. 17, pp. 18091-18097, 2004.
 P. Ranganathan, R. Hamad, R. Mohamed, C. Jayakumar, T. Muthusamy, and G. Ramesh, "Histone deacetylase-mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity," Kidney International, vol. 89, no. 2, pp. 317-326, 2016.
 Y. Shi, L. Xu, J. Tang et al., "Inhibition of HDAC6 protects against rhabdomyolysis-induced acute kidney injury," American Journal of Physiology. Renal Physiology, vol. 312, no. 3, pp. F502-F515, 2017.
 P. Chun, "Therapeutic effects of histone deacetylase inhibitors on kidney disease," Archives of Pharmacal Research, vol. 41, no. 2, pp. 162-183, 2018.
 A. Sato, T. Asano, M. Isono, K. Ito, and T. Asano, "Ritonavir acts synergistically with panobinostat to enhance histone acetylation and inhibit renal cancer growth," Molecular and Clinical Oncology, vol. 2, no. 6, pp. 1016-1022, 2014.
 S. Sharma, P. O. Witteveen, M. P. Lolkema et al., "A phase I, open-label, multicenter study to evaluate the pharmacokinetics and safety of oral panobinostat in patients with advanced solid tumors and varying degrees of renal function," Cancer Chemotherapy and Pharmacology, vol. 75, no. 1, pp. 87-95, 2015.
 W. M. Stadler, K. Margolin, S. Ferber, W. McCulloch, and J. A. Thompson, "A phase II study of depsipeptide in refractory metastatic renal cell cancer," Clinical Genitourinary Cancer, vol. 5, no. 1, pp. 57-60, 2006.
 J. D. Hainsworth, J. R. Infante, D. R. Spigel, E. R. Arrowsmith, R. V. Boccia, and H. A. Burris, "A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma," Cancer Investigation, vol. 29, no. 7, pp. 451-455, 2011.
 S. Y. Wu and C. M. Chiang, "The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation," The Journal of Biological Chemistry, vol. 282, no. 18, pp. 13141-13145, 2007.
 J. Loven, H. A. Hoke, C. Y. Lin et al., "Selective inhibition of tumor oncogenes by disruption of super-enhancers," Cell, vol. 153, no. 2, pp. 320-334, 2013.
 A. Maxmen, "Cancer research: open ambition," Nature, vol. 488, no. 7410, pp. 148-150, 2012.
 L. Wang, X. Wu, R. Wang et al., "BRD4 inhibition suppresses cell growth, migration and invasion of salivary adenoid cystic carcinoma," Biological Research, vol. 50, no. 1, p. 19, 2017.
 X. Zhou, L. X. Fan, D. J. M. Peters, M. Trudel, J. E. Bradner, and X. Li, "Therapeutic targeting of BET bromodomain protein, Brd4, delays cyst growth in ADPKD," Human Molecular Genetics, vol. 24, no. 14, pp. 3982-3993, 2015.
 E. Nicodeme, K. L. Jeffrey, U. Schaefer et al., "Suppression of inflammation by a synthetic histone mimic," Nature, vol. 468, no. 7327, pp. 1119-1123, 2010.
 A. C. Belkina, B. S. Nikolajczyk, and G. V. Denis, "BET protein function is required for inflammation: Brd2 genetic disruption and BET inhibitor JQ1 impair mouse macrophage inflammatory responses," Journal of Immunology, vol. 190, no. 7, pp. 3670-3678, 2013.
 K. Klein, P. A. Kabala, A. M. Grabiec et al., "The bromodomain protein inhibitor I-BET151 suppresses expression of inflammatory genes and matrix degrading enzymes in rheumatoid arthritis synovial fibroblasts," Annals of the Rheumatic Diseases, vol. 75, no. 2, pp. 422-429, 2016.
 B. Suarez-Alvarez, J. L. Morgado-Pascual, S. Rayego-Mateos et al., "Inhibition of bromodomain and extraterminal domain family proteins ameliorates experimental renal damage," Journal of the American Society of Nephrology, vol. 28, no. 2, pp. 504-519, 2017.
 Q. Zhang, J. Qian, and Y. Zhu, "Targeting bromodomain-containing protein 4 (BRD4) benefits rheumatoid arthritis," Immunology Letters, vol. 166, no. 2, pp. 103-108, 2015.
 S. Meng, L. Zhang, Y. Tang et al., "BET inhibitor JQ1 blocks inflammation and bone destruction," Journal of Dental Research, vol. 93, no. 7, pp. 657-662, 2014.
 R. Liu, Y. Zhong, X. Li et al., "Role of transcription factor acetylation in diabetic kidney disease," Diabetes, vol. 63, no. 7, pp. 2440-2453, 2014.
 A. B. Sanz, M. D. Sanchez-Nino, A. M. Ramos et al., "NF-[kappa]B in renal inflammation," Journal of the American Society of Nephrology, vol. 21, no. 8, pp. 1254-1262, 2010.
 A. C. K. Chung and H. Y. Lan, "Chemokines in renal injury," Journal of the American Society of Nephrology, vol. 22, no. 5, pp. 802-809, 2011.
 Z. Zou, B. Huang, X. Wu et al., "Brd4 maintains constitutively active NF-[kappa]B in cancer cells by binding to acetylated RelA," Oncogene, vol. 33, no. 18, pp. 2395-2404, 2014.
 L. Amir-Zilberstein, E. Ainbinder, L. Toube, Y. Yamaguchi, H. Handa, and R. Dikstein, "Differential regulation of NF[kappa]B by elongation factors is determined by core promoter type," Molecular and Cellular Biology, vol. 27, no. 14, pp. 5246-5259, 2007.
 M. Barboric, R. M. Nissen, S. Kanazawa, N. Jabrane-Ferrat, and B. M. Peterlin, "NF-[kappa]B binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II," Molecular Cell, vol. 8, no. 2, pp. 327-337, 2001.
 B. Huang, X. D. Yang, M. M. Zhou, K. Ozato, and L. F. Chen, "Brd4 coactivates transcriptional activation of NF-[kappa]B via specific binding to acetylated RelA," Molecular and Cellular Biology, vol. 29, no. 5, pp. 1375-1387, 2009.
 C. Xiong, M. V. Masucci, X. Zhou et al., "Pharmacological targeting of BET proteins inhibits renal fibroblast activation and alleviates renal fibrosis," Oncotarget, vol. 7, no. 43, pp. 69291-69308, 2016.
 E. Bettelli, T. Korn, M. Oukka, and V. K. Kuchroo, "Induction and effector functions of TH17 cells," Nature, vol. 453, no. 7198, pp. 1051-1057, 2008.
 N. Isailovic, K. Daigo, A. Mantovani, and C. Selmi, "Interleukin-17 and innate immunity in infections and chronic inflammation," Journal of Autoimmunity, vol. 60, pp. 1-11, 2015.
 P. J. Mease, M. C. Genovese, M. W. Greenwald et al., "Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis," The New England Journal of Medicine, vol. 370, no. 24, pp. 2295-2306, 2014.
 T. Y. Park, S. D. Park, J. Y. Cho et al., "ROR[gamma]t-specific transcriptional interactomic inhibition suppresses autoimmunity associated with TH17 cells," Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 52, pp. 18673-18678, 2014.
 D. A. Mele, A. Salmeron, S. Ghosh, H. R. Huang, B. M. Bryant, and J. M. Lora, "BET bromodomain inhibition suppresses TH17-mediated pathology," The Journal of Experimental Medicine, vol. 210, no. 11, pp. 2181-2190, 2013.
 L. Backdahl, A. Bushell, and S. Beck, "Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation," The International Journal of Biochemistry & Cell Biology, vol. 41, no. 1, pp. 176-184, 2009.
 R. Rodrigues-Diez, R. R. Rodrigues-Diez, S. Rayego-Mateos et al., "The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response," Laboratory Investigation, vol. 93, no. 7, pp. 812-824, 2013.
 J. Pindjakova, S. A. Hanley, M. M. Duffy et al., "Interleukin-1 accounts for intrarenal Th17 cell activation during ureteral obstruction," Kidney International, vol. 81, no. 4, pp. 379-390, 2012.
 K. Cheung, G. Lu, R. Sharma et al., "BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice," Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 11, pp. 2952-2957, 2017.
 X. Tang, R. Peng, J. E. Phillips et al., "Assessment of Brd4 inhibition in idiopathic pulmonary fibrosis lung fibroblasts and in vivo models of lung fibrosis," The American Journal of Pathology, vol. 183, no. 2, pp. 470-479, 2013.
 N. Ding, N. Hah, R. T. Yu et al., "BRD4 is a novel therapeutic target for liver fibrosis," Proceedings of the National Academy of Sciences, vol. 112, no. 51, pp. 201522163-201515718, 2015.
 X. Wang, Y. Zhang, X. O. Yang et al., "Transcription of Il17 and Il17f is controlled by conserved noncoding sequence 2," Immunity, vol. 36, no. 1, pp. 23-31, 2012.
 J. I. Spiltoir, M. S. Stratton, M. A. Cavasin et al., "BET acetyllysine binding proteins control pathological cardiac hypertrophy," Journal of Molecular and Cellular Cardiology, vol. 63, pp. 175-179, 2013.
 B. Zhou, J. Mu, Y. Gong et al., "Brd4 inhibition attenuates unilateral ureteral obstruction-induced fibrosis by blocking TGF-[beta]-mediated Nox4 expression," Redox Biology, vol. 11, pp. 390-402, 2017.
 J. Wang, F. Zhou, Z. Li et al., "Pharmacological targeting of BET proteins attenuates radiation-induced lung fibrosis," Scientific Reports, vol. 8, no. 1, p. 998, 2018.
 M. Jung, K. A. Gelato, A. Fernandez-Montalvan, S. Siegel, and B. Haendler, "Targeting BET bromodomains for cancer treatment," Epigenomics, vol. 7, no. 3, pp. 487-501, 2015.
 M. Fontecha-Barriuso, D. Martin-Sanchez, O. Ruiz-Andres et al., "Targeting epigenetic DNA and histone modifications to treat kidney disease," Nephrology Dialysis Transplantation, vol. 33, no. 11, pp. 1875-1886, 2018.
 D. Shlyueva, G. Stampfel, and A. Stark, "Transcriptional enhancers: from properties to genome-wide predictions," Nature Reviews. Genetics, vol. 15, no. 4, pp. 272-286, 2014.
 T. D. Hewitson, S. G. Holt, S. J. Tan, B. Wigg, C. S. Samuel, and E. R. Smith, "Epigenetic modifications to H3K9 in renal tubulointerstitial cells after unilateral ureteric obstruction and TGF-[beta]1 stimulation," Frontiers in Pharmacology, vol. 8, p. 307, 2017.
 G. Sun, M. A. Reddy, H. Yuan, L. Lanting, M. Kato, and R. Natarajan, "Epigenetic histone methylation modulates fibrotic gene expression," Journal of the American Society of Nephrology, vol. 21, no. 12, pp. 2069-2080, 2010.
 G. M. Lefevre, S. R. Patel, D. Kim, L. Tessarollo, and G. R. Dressler, "Altering a histone H3K4 methylation pathway in glomerular podocytes promotes a chronic disease phenotype," PLoS Genetics, vol. 6, no. 10, article e1001142, 2010.
 G. D. Sun, W. P. Cui, Q. Y. Guo, and L. N. Miao, "Histone lysine methylation in diabetic nephropathy," Journal Diabetes Research, vol. 2014, Article ID 654148, 9 pages, 2014.
 J. Gupta, S. Kumar, J. Li, R. Krishna Murthy Karuturi, and K. Tikoo, "Histone H3 lysine 4 monomethylation (H3K4me1) and H3 lysine 9 monomethylation (H3K9me1): distribution and their association in regulating gene expression under hyperglycaemic/hyperinsulinemic conditions in 3T3 cells," Biochimie, vol. 94, no. 12, pp. 2656-2664, 2012.
 A. El-Osta, D. Brasacchio, D. Yao et al., "Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia," The Journal of Experimental Medicine, vol. 205, no. 10, pp. 2409-2417, 2008.
 D. Brasacchio, J. Okabe, C. Tikellis et al., "Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail," Diabetes, vol. 58, no. 5, pp. 1229-1236, 2009.
 S. G. Sayyed, A. B. Gaikwad, J. Lichtnekert et al., "Progressive glomerulosclerosis in type 2 diabetes is associated with renal histone H3K9 and H3K23 acetylation, H3K4 dimethylation and phosphorylation at serine 10," Nephrology, Dialysis, Transplantation, vol. 25, no. 6, pp. 1811-1817, 2010.
 M. Naito, R. A. Zager, and K. Bomsztyk, "BRG1 increases transcription of proinflammatory genes in renal ischemia," Journal of the American Society of Nephrology, vol. 20, no. 8, pp. 1787-1796, 2009.
 R. A. Zager and A. C. M. Johnson, "Renal ischemiareperfusion injury upregulates histone-modifying enzyme systems and alters histone expression at proinflammatory/ profibrotic genes," American Journal of Physiology. Renal Physiology, vol. 296, no. 5, pp. F1032-F1041, 2009.
 J. V. Olsen, B. Blagoev, F. Gnad et al., "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks," Cell, vol. 127, no. 3, pp. 635-648, 2006.
 A. Sharma, K. Singh, and A. Almasan, "Histone H2AX phosphorylation: a marker for DNA damage," Methods in Molecular Biology, vol. 920, pp. 613-626, 2012.
 T. Tanaka, D. Halicka, F. Traganos, and Z. Darzynkiewicz, "Cytometric analysis of DNA damage: phosphorylation of histone H2AX as a marker of DNA double-strand breaks (DSBs)," Methods in Molecular Biology, vol. 523, pp. 161-168, 2009.
 T. Gruosso, V. Mieulet, M. Cardon et al., "Chronic oxidative stress promotes H2AX protein degradation and enhances chemosensitivity in breast cancer patients," EMBO Molecular Medicine, vol. 8, no. 5, pp. 527-549, 2016.
 Z. Ma, Q. Wei, G. Dong, Y. Huo, and Z. Dong, "DNA damage response in renal ischemia-reperfusion and ATP-depletion injury of renal tubular cells," Biochimica et Biophysica Acta (BBA)--Molecular Basis of Disease, vol. 1842, no. 7, pp. 1088-1096, 2014.
 K. Zhu, T. Kakehi, M. Matsumoto et al., "NADPH oxidase NOX1 is involved in activation of protein kinase C and premature senescence in early stage diabetic kidney," Free Radical Biology & Medicine, vol. 83, pp. 21-30, 2015.
 M. Tan, H. Luo, S. Lee et al., "Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification," Cell, vol. 146, no. 6, pp. 1016-1028,2011.
 B. R. Sabari, D. Zhang, C. D. Allis, and Y. Zhao, "Metabolic regulation of gene expression through histone acylations," Nature Reviews Molecular Cell Biology, vol. 18, no. 2, pp. 90-101, 2017.
 O. Ruiz-Andres, M. D. Sanchez-Nino, P. Cannata-Ortiz et al., "Histone lysine crotonylation during acute kidney injury in mice," Disease Models & Mechanisms, vol. 9, no. 6, pp. 633-645, 2016.
 O. Ruiz-Andres, M. D. Sanchez-Nino, J. A. Moreno et al., "Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms," American Journal of Physiology. Renal Physiology, vol. 311, no. 6, pp. F1329-F1340, 2016.
 D. P. Bartel, "MicroRNAs: genomics, biogenesis, mechanism, and function," Cell, vol. 116, no. 2, pp. 281-297, 2004.
 L.-A. MacFarlane and P. R. Murphy, "MicroRNA: biogenesis, function and role in cancer," Current Genomics, vol. 11, no. 7, pp. 537-561, 2010.
 U. A. 0rom, F. C. Nielsen, and A. H. Lund, "MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation," Molecular Cell, vol. 30, no. 4, pp. 460-471, 2008.
 C. L. Jopling, S. Schutz, and P. Sarnow, "Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome," Cell Host & Microbe, vol. 4, no. 1, pp. 77-85, 2008.
 J. Zhang, W. Zhou, Y. Liu, T. Liu, C. Li, and L. Wang, "Oncogenic role of microRNA-532-5p in human colorectal cancer via targeting of the 5'UTR of RUNX3," Oncology Letters, vol. 15, no. 5, pp. 7215-7220, 2018.
 C. Zhang, S. Liang, S. Cheng et al., "Urinary miR-196a predicts disease progression in patients with chronic kidney disease," Journal of Translational Medicine, vol. 16, no. 1, p. 91,2018.
 H. Trachtman, S. Vento, D. Gipson et al., "Novel therapies for resistant focal segmental glomerulosclerosis (FONT) phase II clinical trial: study design," BMC Nephrology, vol. 12, no. 1, p. 8, 2011.
 J. Wu, C. Zheng, Y. Fan et al., "Downregulation of microRNA-30 facilitates podocyte injury and is prevented by glucocorticoids," American Society of Nephrology, vol. 25, no. 1, pp. 92-104, 2014.
 J. T. Park, M. Kato, L. Lanting et al., "Repression of let-7 by transforming growth factor-[beta]1-induced Lin28 upregulates collagen expression in glomerular mesangial cells under diabetic conditions," American Journal of Physiology. Renal Physiology, vol. 307, no. 12, pp. F1390-F1403, 2014.
 B. Wang, J. C. Jha, S. Hagiwara et al., "Transforming growth factor-[beta]1-mediated renal fibrosis is dependent on the regulation of transforming growth factor receptor 1 expression by let-7b," Kidney International, vol. 85, no. 2, pp. 352-361, 2014.
 B. N. Chau, C. Xin, J. Hartner et al., "MicroRNA-21 promotes fibrosis of the kidney by silencing metabolic pathways," Science Translational Medicine, vol. 4, no. 121, article 121ra18, 2012.
 C. L. Lin, P. H. Lee, Y. C. Hsu et al., "MicroRNA-29a promotion of nephrin acetylation ameliorates hyperglycemia-induced podocyte dysfunction," Journal of the American Society of Nephrology, vol. 25, no. 8, pp. 1698-1709, 2014.
 Y. Liu, N. E. Taylor, L. Lu et al., "Renal medullary microRNAs in Dahl salt-sensitive rats: miR-29b regulates several collagens and related genes," Hypertension, vol. 55, no. 4, pp. 974-982, 2010.
 W. Qin, A. C. K. Chung, X. R. Huang et al., "TGF-[beta]/Smad3 signaling promotes renal fibrosis by inhibiting miR-29," Journal of the American Society of Nephrology, vol. 22, no. 8, pp. 1462-1474, 2011.
 C. S. Neal, M. Z. Michael, L. K. Pimlott, T. Y. Yong, J. Y. Z. Li, and J. M. Gleadle, "Circulating microRNA expression is reduced in chronic kidney disease," Nephrology, Dialysis, Transplantation, vol. 26, no. 11, pp. 3794-3802, 2011.
 Z. X. Sheng, H. Yao, and Z. Y. Cai, "The role of miR-146b-5p in TLR4 pathway of glomerular mesangial cells with lupus nephritis," European Review for Medical and Pharmacological Sciences, vol. 22, no. 6, pp. 1737-1743, 2018.
 W. Wang, J. Gao, and F. Wang, "MiR-663a/MiR-423-5p are involved in the pathogenesis of lupus nephritis via modulating the activation of NF-[kappa]B by targeting TNIP2," American Journal of Translational Research, vol. 9, no. 8, pp. 3796-3803, 2017.
 M. Cardenas-Gonzalez, A. Srivastava, M. Pavkovic et al., "Identification, confirmation, and replication of novel urinary microRNA biomarkers in lupus nephritis and diabetic nephropathy," Clinical Chemistry, vol. 63, no. 9, pp. 15151526, 2017.
 M. Ulbing, A. H. Kirsch, B. Leber et al., "MicroRNAs 223-3p and 93-5p in patients with chronic kidney disease before and after renal transplantation," Bone, vol. 95, pp. 115-123, 2017.
 C. G. Lee, J. G. Kim, H. J. Kim et al., "Discovery of an integrative network of microRNAs and transcriptomics changes for acute kidney injury," Kidney International, vol. 86, no. 5, pp. 943-953, 2014.
 L. Amrouche, G. Desbuissons, M. Rabant et al., "MicroRNA146a in human and experimental ischemic AKI: CXCL8dependent mechanism of action," Journal of the American Society of Nephrology, vol. 28, no. 2, pp. 479-493, 2017.
 T. Song, M. Chen, Z. Rao et al., "miR-17-92 ameliorates renal ischemia reperfusion injury," The Kaohsiung Journal of Medical Sciences, vol. 34, no. 5, pp. 263-273, 2018.
 J. G. Godwin, X. Ge, K. Stephan, A. Jurisch, S. G. Tullius, and J. Iacomini, "Identification of a microRNA signature of renal ischemia reperfusion injury," Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 32, pp. 14339-14344, 2010.
 M. Kato, J. Zhang, M. Wang et al., "MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-[beta]-induced collagen expression via inhibition of E-box repressors," Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 9, pp. 3432-3437, 2007.
 A. Krupa, R. Jenkins, D. D. Luo, A. Lewis, A. Phillips, and D. Fraser, "Loss of microRNA-192 promotes fibrogenesis in diabetic nephropathy," Journal of the American Society of Nephrology, vol. 21, no. 3, pp. 438-447, 2010.
 X. Zhong, A. C. K. Chung, H. Y. Chen, X. M. Meng, and H. Y. Lan, "Smad3-mediated upregulation of miR-21 promotes renal fibrosis," Journal of the American Society of Nephrology, vol. 22, no. 9, pp. 1668-1681, 2011.
 A. Zarjou, S. Yang, E. Abraham, A. Agarwal, and G. Liu, "Identification of a microRNA signature in renal fibrosis: role of miR-21," American Journal of Physiology. Renal Physiology, vol. 301, no. 4, pp. F793-F801, 2011.
 N. Dey, F. Das, M. M. Mariappan et al., "MicroRNA-21 orchestrates high glucose-induced signals to TOR complex I, resulting in renal cell pathology in diabetes," The Journal of Biological Chemistry, vol. 286, no. 29, pp. 25586-25603, 2011.
 L. Denby, V. Ramdas, M. W. McBride et al., "miR-21 and miR-214 are consistently modulated during renal injury in rodent models," The American Journal of Pathology, vol. 179, no. 2, pp. 661-672, 2011.
 B. Du, L. M. Ma, M. B. Huang et al., "High glucose downregulates miR-29a to increase collagen IV production in HK-2 cells," FEBS Letters, vol. 584, no. 4, pp. 811-816, 2010.
 K. Bhatt, L. L. Lanting, Y. Jia et al., "Anti-inflammatory role of microRNA-146a in the pathogenesis of diabetic nephropathy," Journal of the American Society of Nephrology, vol. 27, no. 8, pp. 2277-2288, 2016.
 H. Y. Chen, X. Zhong, X. R. Huang et al., "MicroRNA-29b inhibits diabetic nephropathy in db/db mice," Molecular Therapy, vol. 22, no. 4, pp. 842-853, 2014.
 J. Guo, J. Li, J. Zhao et al., "MiRNA-29c regulates the expression of inflammatory cytokines in diabetic nephropathy by targeting tristetraprolin," Scientific Reports, vol. 7, no. 1, p. 2314, 2017.
 A. Gholaminejad, H. Abdul Tehrani, and M. Gholami Fesharaki, "Identification of candidate microRNA biomarkers in renal fibrosis: a meta-analysis of profiling studies," Biomarkers, vol. 18, pp. 1-12, 2018.
Jose Luis Morgado-Pascual, (1,2) Vanessa Marchant [ID], (3,4) Raul Rodrigues-Diez [ID], (2,5) Nuria Dolade, (2,6) Beatriz Suarez-Alvarez, (2,7) Bredford Kerr, (3) Jose M. Valdivielso, (2,6) Marta Ruiz-Ortega [ID] (1,2) and Sandra Rayego-Mateos [ID] (2,6)
(1) Cellular Biology in Renal Diseases Laboratory, Universidad Autonoma Madrid, IIS-Fundacion Jimenez Diaz, Madrid, Spain
(2) RedInRen RETIC, ISCIII, Spain
(3) Centro de Estudios Cientficos (CECs), Valdivia 5110466, Chile
(4) Faculty of Medicine, Universidad Austral de Chile, Valdivia 5090000, Chile
(5) Nephrology Department, IDIPAZ, Madrid, Spain
(6) Vascular and Renal Translational Research Group, Institut de Recerca Biomedica de Lleida IRBLleida, Lleida 25198, Spain
(7) Translational Immunology Laboratory, Health Research Institute of the Principality of Asturias (ISPA), Hospital Universitario Central de Asturias, Oviedo, Spain
Correspondence should be addressed to Sandra Rayego-Mateos; firstname.lastname@example.org
Received 15 July 2018; Revised 31 October 2018; Accepted 5 November 2018; Published 13 December 2018
Academic Editor: Agnieszka Dobrzyn
Caption: Figure 1: The main epigenetic changes associated with clinical and experimental renal damage such as DNA methylation (DNAme), histone posttranslational modifications, and miRNAs.
Caption: Figure 2: Summary of different therapeutic approaches in experimental renal damage related to DNAme and histone modifications.
Caption: Figure 3: The action mechanism of the BET inhibitor JQ1, in the regulation of inflammation, Th17 response, and fibrosis.
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|Author:||Morgado-Pascual, Jose Luis; Marchant, Vanessa; Rodrigues-Diez, Raul; Dolade, Nuria; Suarez-Alvarez,|
|Publication:||Mediators of Inflammation|
|Date:||Jan 1, 2018|
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