Brain-derived neurotrophic factor (BDNF) is a major neurotrophin whose loss or interruption is well established to have numerous intersections with the pathogenesis of progressive neurological disorders. There is perhaps no greater example of disease pathogenesis resulting from the dysregulation of BDNF signaling than Huntington’s disease (HD)—an inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive impairments associated with basal ganglia dysfunction and the ultimate death of striatal projection neurons. Investigation of the collection of mechanisms leading to BDNF loss in HD highlights this neurotrophin’s importance to neuronal viability and calls attention to opportunities for therapeutic interventions. Using electronic database searches of existing and forthcoming research, we constructed a literature review with the overarching goal of exploring the diverse set of molecular events that trigger BDNF dysregulation within HD. We highlighted research that investigated these major mechanisms in preclinical models of HD and connected these studies to those evaluating similar endpoints in human HD subjects. We also included a special focus on the growing body of literature detailing key transcriptomic and epigenetic alterations that affect BDNF abundance in HD. Finally, we offer critical evaluation of proposed neurotrophin-directed therapies and assessed clinical trials seeking to correct BDNF expression in HD individuals. Huntington’s disease (HD) is a universally fatal, autosomal-dominant neurodegenerative disease that affects nearly 40,000 individuals in the United States. This “hereditary chorea,” first fully described and reported by George Huntington in 1872, typically affects individuals in middle age and results in their death within 20 years . AccordiHTT) gene on chromosome 4, which encodes a mutant protein (mHTT) with an N-terminal polyglutamine repeat expansion [HTT generally correlates inversely with age-of-onset of HD motor symptoms [The neuronal atrophy in HD is the consequence of a CAG trinucleotide repeat expansion occurring in exon 1 of the huntingtin  of the caudate and putamen, two subregions of the basal ganglia that have a shared canonical role in the control of voluntary movements and suppression of involuntary movements. It is near-universally accepted that the initial loss of D2 dopamine receptor-expressing MSNs of the indirect pathway of movement generates the distinctive chorea in the early stages of manifest HD ,15. EmerIn addition to the movement disorder manifest in HD individuals, it is also well-established that cognitive impairments and affective symptoms are highly co-morbid with HD and often occur prior to the onset of overt HD chorea . This obThe examination of molecular features associated with mHTT expression has generated significant insight into specific cytological disruptions present at multiple stages of HD and in corresponding HD models. These include impairments of the regulation of gene expression , translaNTR heteromeric receptor complexes. For this reason, exposure to neurotrophins, whether constitutive or activity-associated, is strongly supportive of neuron structure and function and can often determine a neuron’s capacity to withstand exposure to neurotoxic stimuli. BDNF and BDNF-responsive neurotrophin receptors are reviewed extensively in this special issue and in recent literature reviews [BDNF is a member of the neurotrophin family, a small but critically important series of diffusible neuropeptides with countless roles in neuronal development, survival, and function, including synaptic plasticity. Neurotrophins engage major neuronal growth and anti-apoptotic signaling cascades through action at either tropomyosin-receptor kinase (Trk) or Trk-p75 reviews ,47,48. NBDNF gene, but it may also exist as a result of disruption of the proteolysis of its precursor, proBDNF, or through the altered metabolism of its mature isoform [Landmark studies in multiple neurodegenerative fields have repeatedly demonstrated shared impairments of neurotrophin homeostasis in human subjects and rodent models. These impairments most often include the regional downregulation of BDNF expression in affected neural structures ,50 or in isoform ,55. To c isoform ,56. In t isoform . NonetheD) are largely acknowledged to occur between NGF:TrkA, BDNF and NT4:TrkB, and NT3:TrkC complexes. The activation of Trk family receptors is anti-apoptotic in nearly all contexts through the activation of major cell signaling pathways in neurons, including, but not limited to, PI3K/AKT and Ras/MAPK/ERK [NTR), forms Trk-p75NTR heteromeric complexes with an exceptionally high affinity for neurotrophins [NTR also forms a co-receptor complex with sortilin and drives pro-atrophic signaling through the high-affinity binding of proneurotrophins [NTR and pro- and mature neurotrophin expression. The marked and broad downregulation of Trk expression has nevertheless been described in numerous research reports involving major neurodegenerative diseases [The Trk family of neurotrophin receptors has likewise attracted considerable research attention for its role as the major signal transducer system for mature neurotrophins. While the affinity between neurotrophins and neurotrophin receptors is somewhat promiscuous, the strongest bindings  ,86. At lA decline in BDNF expression is not only observed in HD individuals but is reproduced consistently within HD models. In fact, the expression profiling of striatal tissue obtained from two HD models, when compared to humans, indicated that BDNF depletion may represent the most critical role underlying striatal degeneration in HD individuals . In agreCuriously, loss of BDNF is even observed in neuroanatomical structures largely spared by classical HD pathology, although it is unknown if the majority of these observations are restricted to models. In both HD individuals and the N171-82Q model, BDNF expression is sharply reduced in the pontine and medullar regions of the brainstem and was suggested to contribute to accelerated heart rate. Intracerebroventricular administration of BDNF was sufficient to restore the heart rate to normal levels in these HD mice . DisruptBdnf gene expression well before decrements in measures of viability [BDNF appeared within dysregulated gene networks in some iPSC models [BDNF or NTRK2 (TrkB) gene expression between HD and control groups, but HD neurons displayed neurite dysmorphogenesis and electrophysiological abnormalities—two neuronal attributes associated with neurotrophin signaling [Q111/111 striatal cells displayed both reduced expression and subcellular localization of TrkB and impaired BDNF-induced MAPK signaling vs. cells of the STHdhQ7/7 control line [Modeling of HD within in vitro systems largely mirrors the decline in BDNF abundance in rodent models and HD individuals. Indeed, mouse primary neuron models that employ the lentiviral transduction of mHTT exon 1 display the downregulation of iability ,105. Untiability ,107,108.iability . BDNF apC models , and theC models . In suppC models . Anotherignaling . Finallyrol line . UltimatCAG140 neurons [HTT’s role as a scaffolder of molecular motor complexes and their cargoes places it in a pivotal intersection to disrupt BDNF’s functions at distal neuronal structures, as anterograde and retrograde axonal transport is critically linked with neurotrophin release and signal transduction. Microfluidic and real-time imaging approaches employing neurons obtained from HD models have been particularly illuminating in examining trafficking deficits in mHTT-expressing neurons. Indeed, a decrease in BDNF travel length and the speed of BDNF-containing vesicles was observed in primary neurons obtained from zQ175 HD model mice . BDNF-sp neurons  and othe neurons . A corre neurons , indicat neurons . Interes neurons . Retrogr neurons . Finally neurons . Phospho neurons . There is perhaps no greater purpose associated with BDNF than its repertoire of roles at the synapse, where BDNF signaling is firmly established as a critical factor shaping synaptic development, structure, and function . Loss ofQ175-expressing cortical projection neurons [Q111/111 cell model had differential effects on gene expression associated with synaptic plasticity vs. controls, including a lack of a compensatory Bdnf and Arc upregulation [There are likely effects of mHTT on synaptic function that may be mediated by the loss of synaptic BDNF expression or involve additional knock-on effects of altered BDNF-TrkB signaling in HD. Early evidence for a causal role for BDNF in deficits of synaptic efficacy was provided by two groups demonstrating that the overexpression or exogenous administration of BDNF in HD models partially rescues deficits in long-term potentiation (LTP), a major model of synaptic plasticity ,124. Xie neurons . Finallygulation . NTR at the synapse of hippocampal neurons in two mouse models of HD [NTR therefore likely co-exists with decrements in synaptic TrkB expression and favors the activation of pro-atrophic/pro-apoptotic neuronal signaling cascades in humans and models [There is limited but exciting evidence that the synaptic expression of neurotrophin receptors is similarly compromised in HD. Reduced expression of TrkB in HD mouse models and in HD individuals was first reported nearly two decades ago, although it was not clear whether this decrement was neuron-wide or specific to synaptic terminals, a critical site of TrkB expression . Evidencls of HD . This upd models . When coHTT allele in HD likely contributes to the simultaneous exacerbation of decrements of BDNF expression and neurotrophin signaling at the synapse. In agreement with this observation, many pathological processes are reversed by the overexpression of wild-type HTT protein, indicating that loss of normal HTT function in adulthood may promote an equally damaging outcome as the expression of its mutant counterpart [It is important to note that various research groups have identified roles for HTT at the synapse that are independent of BDNF, including the scaffolding of multiple cytoskeletal and synaptic vesicle proteins and the regulation of vesicle endocytosis ,134,135.nterpart ,140.HTT/mHTT gene regulatory networks have now grown to staggering scales. Wild-type HTT is known to interact with several transcription factors (TFs) [HTT gene dosage on the degree or number of transcriptional alterations [BDNF is a central feature of HD molecular pathology [A central molecular feature of HD pathogenesis is the robust transcriptional dysregulation observed in affected cells, which occurs even in premanifest stages of HD ,141. Forrs (TFs) , but a merations . Insteaderations ,145. Alterations ,147. Theathology . ConsequBDNF gene in both rodents and humans is extraordinarily complex [Bdnf transcripts by neurons in precise spatiotemporal patterns [Bdnf gene. The Bdnf architecture includes multiple 5′ noncoding exons and one exon containing the pre-proBDNF coding sequence. Each of these 5′ non-coding exons is linked to separate promoters. Additionally, multiple untranslated regions downstream (3′-) of the Bdnf coding sequence are known to be involved in the regulation of transport of the mature transcript [BDNF gene expression in neurons is partially, but directly, regulated by wild-type HTT through its interaction with a transcriptional repressor, the repressor-element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF). Wild-type HTT sequesters REST/NRSF in the cytoplasm, preventing it from binding to a corresponding response element or neuron-restrictive silencer element (RE1/NRSE) within promoter II of Bdnf, thereby facilitating Bdnf transcription [BDNF promoter and represses its transcription  the genetic sequence encoded within the DNA itself, this series of transcriptional control mechanisms serves to affect gene transcription in both heritable and non-heritable manners. Histone post-translational modification (PTM) and DNA methylation, two forms of epigenetic regulation, have both been connected to altered expression of genes in HD. Therefore, the robust and profound disruption of gene expression in HD may arise from the failure of epigenetic control in affected neuronal populations. A greater understanding of epigenetic regulation and its failure in HD illuminates several potential areas for research and therapy.Histone PTMs are the set of covalent alterations that occur at certain residues on the N-terminal tails of histone octamers, the core structural components of nucleosomes. These reversible modifications, which may include acetylation, ubiquitination, methylation, phosphorylation, and SUMOylation, serve to define gene expression . For exaBDNF? Research examining histone PTM ratios in humans and models has consistently reported the differential expression of both repressive [BDNF transcription in HD, even when the expression of other neuron-critical genes is restored. A study has reported the enrichment of an active histone PTM (H3K4me3) at BDNF regulatory regions in mouse and human brains, which were downregulated in the HD context, and a corresponding rescue in gene expression was observed when the demethylase catalyzing this mark was inhibited in a Drosophila model [Bdnf promoter occupancy and regulates Bdnf transcription [BDNF expression [Bdnf expression by rescuing transport deficits through non-epigenetic mechanisms that target non-histone substrates. For example, HDAC6 inhibition, by increasing the levels of α-tubulin acetylation, has been demonstrated to rescue axonal transport deficits in other neurodegenerative diseases and was recently evaluated in two HD preclinical models [BDNF expression in HD models. Indeed, both focused molecular and larger-omics approaches evaluating transcriptomic endpoints under the non-selective inhibition of HDACs failed to detect (or did not report) changes for Bdnf expression [Bdnf transcription, but act via the engagement of other gene expression mechanisms, including via coupling with alternative epigenetic regulatory processes. In fact, gene expression analyses of progeny from HDAC inhibitor-treated male HD mice showed improved HD phenotypes vs. vehicle controls through the mechanism involving altered DNA methylation patterning [How might histone modifications be altered in HD to contribute to gene expression dysregulation, including that of pressive ,166 and pressive ,169,170 cription ; howeverpression ,168. Thel models ,173. Thepression ,175,176.tterning . The inhBdnf includes multiple promoters, and at least promoter IV is differentially methylated in HD model cortical neurons vs. controls, providing a putative but direct explanation for dysregulated Bdnf transcription  is a well-characterized epigenetic mark that is associated with gene repression when present at promoters and regulatory regions. Approximately 75% of the CpGs (cytosine-guanine dinucleotides) in neurons possess the 5mC mark . “CpG iscription B [104,10otrophin ,181. Sevromoters ,183,184.romoters . This prel of HD B. Bdnf [2A receptor (A2AR) gene body. This outcome was recapitulated in the R6/1 and R6/2 models, which correlated with decreased striatal expression of A2AR in these mice [2AR is a receptor whose activity is known to maintain BDNF levels in the CNS and can stimulate TrkB expression [BDNF gene throughout developmental timeframes remains an unexplored research question that may have exciting implications, given the wide array of BDNF neurodevelopmental functions.5mC is not removed directly in post-mitotic cells but via a series of ten-eleven translocation (TET1)-dependent enzymatic conversions which include 5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine . These aBdnf ,189. A sese mice . This fipression . In factpression . Prenatapression . In supppression . The extBDNF gene expression in HD. Splicing of pre-mRNAs into mature transcripts has only recently been shown to be broadly dysregulated in HD, an observation which could have a significant impact on Bdnf and genes with similarly complex genomic structure. Research reports detailing exon skipping, cryptic exon exposure, and intron retention are not infrequently reported in HD brains and models [mHTT gene itself (but not wild-type HTT) is mis-spliced in HD individuals and knock-in models, which results in the synthesis of a transcript encoding only the pathogenic exon 1 fragment [Bdnf transcript in HD models. A growing body of research, however, has illuminated mHTT inclusion sequestration and mis-localization of the activity of the well-known splicing factor transactive response DNA-binding protein of 43kDa (TDP-43) in HD [Still, other intriguing explanations have been proposed for the decrements in d models ,196,197.fragment ,199. Thi3) in HD ,201. TDP3) in HD .BDNF silencing [BDNF lies at a critical hub of the miRNA-mRNA regulatory network formed by these miRNAs and, intriguingly, that two of these miRNAs (miR-10b-5p and miR-30a-5p) have putative targets in the 3′UTR of the BDNF transcript [BDNF expression through an in silico approach but has not yet been demonstrated in living systems [Bdnf expression in HD models through the restoration of other modes of gene regulation discussed above [BDNF transcription can also serve to restrain BDNF transcription in vitro and in vivo through the expression of long non-coding natural antisense transcripts (NATs). Knockout of the NAT for Bdnf can enhance cognitive function through the disinhibition of the antisense-mediated decay of the Bdnf transcript, but the manipulation of NAT expression has not yet been attempted in the context of HD [MicroRNAs (miRNAs), owing to their critical post-transcriptional regulatory role, have come under particular scrutiny for a putative role in ilencing ,204. Somilencing ,206. A uanscript . The upr systems . Other med above . Antisenxt of HD ,209. To date, no single therapeutic strategy has shown to be effective in the reduction or delay of classical signs of HD progression in humans. The existing tetrabenazine-based FDA-approved pharmacotherapies for use in HD largely target the reduction of choreic movements in HD through the inhibition of the vesicular monoamine transporter 2 (VMAT2), but they are insufficient to mitigate HD pathophysiology . The ideBdnf cDNA under the control of an astrocytic promoter, when injected into the striatum of R6/2 mice, was shown to delay the onset of HD-specific behavioral abnormalities. This effect may be related to increased neostriatal neurogenesis rather than the reduction of MSN death, as BDNF overexpression through AAV approaches has been shown to increase doublecortin immunoreactivity in R6/2 mice [NTR in the context of reduced TrkB expression may instead exacerbate disease-specific outcomes in HD patients and disease models. For these reasons, these “direct” strategies have largely failed to gain practical success outside of preclinical models.For some time, the utilization of BDNF supplementation or direct treatment has been considered as a therapeutic approach for addressing neurodegenerative disease. Accordingly, many of these approaches have been evaluated in HD models. Limited preclinical research indicates that chronic systemic BDNF delivery through indwelling osmotic pumps increased the synthesis of BDNF in the CNS and diminished some measures of disease progression in R6/2 mice ,211. A s6/2 mice . Other n6/2 mice . It is iQ140 mice resulted in improved motor and electrophysiological deficits in these models, thought to be facilitated by increased BDNF production [Engineered mesenchymal stem cell (MSC) transplant is under growing consideration as a therapeutic agent in HD for their neural repair properties, which are partially connected with their constitutive ability to release BDNF. At least three groups have reported that the intravenous treatment of MSC-like human dental pulp stem cells possesses the ability to alleviate key HD-like pathological features in the 3-nitropropionic (3-NP) rat HD model ,218,219.oduction . One repoduction . Anotheroduction . It is woduction ,225. More indirect and less-invasive experimental manipulations that serve to broadly up-regulate BDNF may alleviate disease progression and offer immediate insight for the clinical management of HD in humans. Exercise enrichment, a modification which is well-connected to a beneficial CNS-wide BDNF response, was sufficient to rescue the loss of BDNF in the hippocampus and striatum of R6/1 mice . AccordiBdnf transcription [2AR agonist inosine mitigated 3-NP-induced motor abnormalities and body weight loss by increasing BDNF signaling through the TrkB-ERK-CREB pathway [NTR [The repurposing of emerging small molecule compounds, especially those aimed at alleviating impairment in key cellular pathways, may also indirectly up-regulate BDNF or its signaling and therefore offer similar promise to more direct pharmacotherapies in HD. For example, at least two groups have evaluated the metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268 in preclinical HD models for its enigmatic BDNF-stimulating property ,233. Somcription . Other g pathway . Another pathway . Other s pathway ,237, p75way [NTR , and RESway [NTR  have alsThe use of the sigma-1 receptor (S1R) agonist pridopidine is under increasing consideration for the treatment of HD. Pridopidine was shown to promote a significant increase in BDNF axonal trafficking, TrkB signaling at the synapse, and enhanced release of glutamate, albeit within a reconstituted “brain-on-a-chip” model of HD . A bulk Still, other research terms have engineered novel peptidergic compounds that specifically modify BDNF expression. Two intriguing reports from Couly et al. indicated that a 23 amino acid peptide “P42” constructed from HTT, when delivered systemically over several weeks, was sufficient to rescue deficits in Schaffer collateral LTP and had modest effects in restoring motor function in the R6/2 model. These effects were suggested to be related to the up-regulation of BDNF and increasing activity at TrkB in P42-treated mice, although it is still unclear the set of cellular mechanisms by which this effect was produced . SomewhaThe dysregulation of BDNF is a well-documented and significant molecular alteration in HD and plays a critical role in its pathogenesis. Substantial evidence suggests that reduced BDNF trophic support and impaired TrkB signaling underlie the degeneration of striatal projection neurons, the most vulnerable cell type in HD. A deeper understanding of the mechanisms leading to deficits in BDNF-TrkB signaling is essential for developing effective neuroprotective treatments for HD. Despite continued research into neuron-protective factors for use in neurodegenerative diseases, neurotrophin-based therapeutic approaches have yet to gain serious attention in clinical practice. The set of challenges restraining the identification and development of CNS pharmacotherapeutics is exemplified by BDNF. These practical hurdles include poor half-live in vivo, off-target effects, and poor blood–brain barrier (BBB) penetrability. Drugs that aim to target BDNF expression in vivo must also overcome these obstacles. Still, there currently appears to be more promise for neurotrophin-based therapies in HD than in recent history, owing to advances in the understanding of BBB physiology. Improvements in CNS drug delivery methods, including transcranial focused ultrasound-induced permeabilization ,249, nasBDNF expression in neurons and thereby provide benefits to neuronal health [HTT targeting, rather than the broad silencing of wild-type and mutant HTT transcripts, given the growing repertoire of observed wild-type HTT neural functions related to BDNF. The continued improvement in allele-selective ASO design and delivery will undoubtedly have considerable implications for HD.Due to the complexities involved with neurotrophin drug delivery, and the monogenic nature of HD, many compounds investigated within the HD clinical trial pipeline to date did not target BDNF or TrkB directly, but instead acted on mHTT expression itself. It is suspected, but not yet established, that the downregulation of mHTT or reduction of mHTT aggregation through RNA interference may indirectly increase l health . The adml health . HTT-lowIn the present review, we illustrated numerous ways in which BDNF expression, transport, and release are compromised in HD. However, there remains much to be uncovered in relation to the intersection of BDNF dysregulation and HD. For example, questions revolving around the ability of BDNF to modulate CNS inflammation associated with HD remain underinvestigated. The nature of the glial inflammatory response in the presence of reduced BDNF in HD may be an especially important research direction because some neurotrophins, including BDNF, appear to temper the glial inflammatory response to favor anti-inflammatory modes of activation in certain models ,255,256.HD remains an incredibly challenging neurodegenerative disease to address because of the paucity of available molecular targets and lack of suitable therapeutic intervention strategies. Although a few FDA-approved pharmacotherapies exist to manage the classic choreic symptoms coupled with HD, none are able to slow or prevent HD pathogenesis. Therefore, candidate approaches involving broadly protective factors may prove to be crucial disease-modifying treatments for HD individuals. BDNF is a neurotrophin that is critically intertwined with an array of vital neuronal signaling pathways through TrkB. BDNF-TrkB signaling is strongly supportive of neuronal resilience, longevity, and normal function. The loss of BDNF in HD therefore provides both an explanation for the array of molecular, functional, and cognitive outcomes that manifest in HD as well as a potential pathway for treatment. Here, we extensively discussed multiple major HD mechanisms that have a shared outcome of neural BDNF reduction. We provided a special focus on the epigenetic and transcriptional dysregulation of BDNF in HD, a critical characteristic of its early molecular pathogenesis. Finally, we offered a critical analysis of emerging therapeutic approaches involving this neurotrophin within HD. Despite the promise of neurotrophin-based therapeutic approaches, there unfortunately remain major practical obstacles for their future use. These include delivery to deep neuroanatomical structures, poor pharmacokinetic profile, and uncertain efficacy in humans. Emerging viral-based strategies, Trk agonists, and brain-penetrant small molecules or peptides may soon overcome these challenges. Ultimately, we propose that neurotrophin therapies will likely form part of a multi-pronged series of interventions for HD involving lifestyle modification, symptomatic treatment, and small molecule-based approaches to modify disease progression. Sources included in this literature review were populated from three major literature databases: Pubmed, Web of Science (Thompson Routers), and Scopus. These databases were supplemented from multiple gray literature sources, including Google Scholar, clinicaltrials.gov, EU Clinical Trials Register, and the bioRxiv preprint server. Our search strategy involved Boolean strings constructed from MeSH terms . These search strings were complemented by plain text searching within the MeSH string results, the examination of cross-referenced sources, and personal knowledge of relevant articles. Each of the authors independently executed these literature searches and prioritized articles that were published in the previous 5 years. There were no a priori inclusion or exclusion criteria.


Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. The pathogenesis of DKD is multifactorial, with several molecular pathways implicated. Recent data suggest that histone modification plays an important role in the development and progression of DKD. Histone modification appears to induce oxidative stress, inflammation and fibrosis in the diabetic kidney. In the present review, we summarize the current knowledge on the association between histone modification and DKD. Chronic kidney disease (CKD) affects 9.1% of the population worldwide and is an important cause of morbidity and mortality . Even inEpigenetic mechanisms include DNA methylation, histone modification, and microRNA (miRNA) . HistoneThe defining histopathologic features of DKD are glomerular basement membrane (GBM) thickening, mesangial matrix expansion, nodular glomerulosclerosis and tubular and vascular lesions . p21 plaIntrarenal oxidative stress is another feature of DKD ,35. OxidAutophagy represents a mechanism of preservation of podocyte integrity . CompromDKD is also characterized by the accumulation of extracellular matrix (ECM) proteins, collagen, laminin and fibronectin, in the glomerulus and the renal tubulointerstitium, which ultimately lead to glomerulosclerosis and tubulointerstitial fibrosis . The patSeveral immune cells of both the innate and adaptive immune system also contribute to renal injury in DKD ,19. In aAdvanced glycation end-products (AGEs) induced by hyperglycemia play an important role in the pathogenesis of DKD ,44. AGEsIn patients with diabetes mellitus, the production of TGF-β is increased in the kidney, which then facilitates the development of early manifestations of DKD . TGF-β wEpithelial-to-mesenchymal transition (EMT), which occurs in tubular cells after injury, refers to a change in phenotype that is characterized by the conversion of epithelial markers to mesenchymal features and generates kidney fibrosis . The dowHistone modifications regulate gene transcription, DNA repair and DNA replication ,56. PostThere is accumulating evidence that PTMs are involved in the regulation of genes associated with the pathogenesis of diabetes ,8. The PHistone acetylation can unravel chromatin and enable the binding of transcription factors and cofactors that lead to gene expression . HistoneStudies in db/db diabetic mice reported that early glomerulosclerosis was associated with reduced histone H3K9 and H3K23 acetylation . Other sIn the context of hyperglycemia, increased H3K9 and H3K18 acetylation levels in the mesangial cells were associated with the production of inflammatory mediators including MCP-1, ICAM-1, VCAM-1 and inducible nitric oxide synthases (iNOS) . FurtherS)-hydroxyeicosatetraenoic acid (12(S)-HETE), an oxidized lipid which promotes oxidative stress, induced profibrotic gene expression in association with the augmented enrichment of their promoter by H3K9Ac and H3K4me in rat mesangial cell [The enrichment of H3K9/14Ac at the promoters of PAI-1 and p21 genes in rat mesangial cells exposed to hyperglycemia and glomeruli from diabetic mice were associated with the increased expression of these genes . In addiial cell . In mesaial cell . In vitrial cell . In addiial cell . In anotial cell .Blockade of HDAC4 signaling increased the H3K9Ac levels in the miR-29a proximal promoter and miR-29a transcription in hyperglycemia-treated podocytes and attenuated the hyperglycemia-induced apoptosis . In anotHyperglycemia-induced Txnip expression was associated with the enrichment of H3K9ac at the promoter region of the gene in the kidneys of diabetic mice . ChIP asHistone methylation takes place in arginines, lysines and histidines on histone tails . HistoneKDM6A expression was increased and H3K27me2/3 levels were decreased in the kidneys of diabetic mice  and in hPalmitic acid (PA) stimulation decreased the enrichment of H3K27me3 on the promoters of IL1b and IL6, whereas the overexpression of KDM6A further decreased H3K27me3 levels on their promoters in renal mesangial cells . In contEdn1, which encodes endothelin-1 [Edn1 transcription [Edn1 transcription [The levels of H4K20me1, a downstream target of KMT5A, decreased in hyperglycemia-treated HUVECs and the levels of H4K20me1 were enriched in the promoter region of enolase 1 (ENO1), regulating the ENO1 levels and thereby inducing EndMT . On the thelin-1 . Moreovecription . Notablycription .In the kidneys of diabetic mice, hyperglycemia-induced Txnip expression was associated with the stimulation of activating histone marks H3K4me3 and H3K4me1, as well as with a decrease in the repressive histone mark H3K27me3 at the promoter of the gene . In anotTGF-β1 stimulated the expression of the p21 gene in rat mesangial cells, while the levels of H3K9me2/3 and H3K4me1/2/3 at p21 gene promoter were correlated with p21 gene expression . SimilarSIRT-6 induction of activated protein kinase (AMPK) signaling, through H3K9 and H3K56, contributed to hyperglycemia-induced mitochondrial dysfunction and apoptosis in podocytes . In anotHistone modification appears to play an important role in the pathogenesis of DKD. Indeed, histone acetylation and methylation are implicated in the propagation of inflammation, oxidative stress and fibrosis in the kidney. Even though the exact mechanism(s) through which impaired epigenetic landscape contributes to DKD is still unclear, it appears that an altered enhancer landscape plays an important role ,113,114.