dn is one of the most serious diabetic microvascular complications and the leading cause of end - stage renal diseases ( esrd ) ; it brings about heavy social and economic burden worldwide , particularly in the developed countries .
both type 1 and type 2 diabetic patients presented indistinguishable and variable pathological changes and clinical course ; the prognosis is difficult to predict because of diverse pathogenesis .
clinically , dn is characterised by different degrees of proteinuria , albuminuria , increased serum creatinine ( scr ) , decreased glomerular filtration rate ( gfr ) , and esrd [ 1 , 2 ] .
importantly , dn also increases the risks for the development of diabetic macrovascular complications including heart attacks and strokes [ 3 , 4 ] .
pathologically , dn associated histological structural changes include glomerular mesangial expansion , glomerular basement membrane ( gbm ) thickening , glomerular sclerosis known as kimmelstiel - wilson lesions caused by excessive extracellular matrix ( ecm ) proteins accumulations , and tubulointerstitial fibrosis in the advanced stages [ 1 , 5 ] .
arterial hyalinosis of the afferent and efferent arterioles is often prevalently caused by endothelial dysfunction and inflammation [ 2 , 6 , 7 ] , which will lead to glomerular hyperfiltration . in the development and progression of dn , resident kidney cells are affected by hyperglycemia : including mesangial cells , podocytes , endothelial cells , smooth muscle cells , inflammatory cells , myofibroblasts , and cells of tubular and collecting duct system .
multiple contributors including environmental and genetic factors are associated with the pathogenesis of dn , which cause metabolic , hemodynamic , and biochemical changes in the diabetic kidneys .
main pathways leading to dn include intracellular pkc activation and increased polyol pathway flux , production of reactive oxygen species ( ros ) and advanced glycation end products ( ages ) , and hypertension and glomerular hyperfiltration leading to shear stress and mechanical stretch [ 8 , 9 ] .
increased blood glucose activates the renin - angiotensin system ( ras ) , tgf--smad - mapk pathway , jak - stat pathway , and g - protein signaling ; aberrant expression of ecm proteins and deregulated expression of cyclin kinases and their inhibitors ; transcription factor such as nf-b , proinflammatory cytokines like tnf and il-1 , and toll - like receptors 4 ( tlr4 ) , which are considered to exert hemodynamic , proinflammatory , and profibrotic effects on kidney cells [ 8 , 13 ] .
there is cross - talk among the above - mentioned signaling pathways , which can amplify aberrant pathogenetic genes expression and lead to the progression of dn .
in addition , the phenomenon of metabolic memory regulated by epigenetic mechanisms can promote these genes expressions [ 14 , 15 ] . although a lot of biochemical and molecular mechanisms and pathways have been broadly studied in the pathogenesis of dn
, the undeniable fact is that the progressive incidence and prevalence of dn worldwide still exist , suggesting that more investigations will be needed in the future .
emerging evidences suggest that multiple signaling pathways activations and key transcription factors ( tfs ) are associated with the pathophysiology of dn , which could be influenced by epigenetically regulated mechanisms in chromatin ( histones form a complex structure with dna ) , including dna methylation , posttranslational modifications ( ptms ) , and noncoding rnas ( ncrna ) , which can modulate gene expression in the cell - type - specific pattern .
core histones are subject to diverse ptms including histone lysine acetylation ( hkac ) , histone lysine methylation ( hkme ) , phosphorylation , ubiquitination , and sumoylation . we have implicated the roles of hkme in the pathogenesis of dn , especially in the metabolic memory phenomenon pertinent to dn [ 2 , 16 , 17 ] .
global acetylation alterations have been seen in a lot of human diseases including cancer and nervous system diseases , whereas the roles of hac in the pathogenesis of dn are rarely mentioned .
recently , some studies showed that hac level is linked to dn , hats and hdacs also participate in the pathogenesis of dn , and the research regarding hac and the covalent enzymes is not enough to yield a clear picture about dn so far . in this review , we describe some progress associated with the molecular mechanism underlying dn , with specific emphasis on hac and acetylation on nonhistone proteins as important regulators of gene expression in renal cell under diabetic conditions ; the regulators of hac such as hats as well as hdacs in the development and progression of dn ; the inhibitors of hats / hdacs in the dn pathogenesis and their therapeutic potentials for dn .
dynamic balance of histone acetylation and deacetylation can regulate gene expression , chromosome assembly , mitosis , and ptms , by altering the chromatin structure and the accessibility to tfs without affecting the sequence of dna .
hac is highly reversible and dynamic , which can be catalyzed by hats or hdacs , respectively .
hkac at n - terminal tails can facilitate gene transcription through neutralizing the positive charge of histone residues and weakening the binding of histone to negatively charged dna [ 22 , 23 ] .
hkac , such as h3k9ac , h3k14ac , and h4kac , is generally linked to permissive gene expression , while histone deacetylation is often associated with chromatin condensation and gene transcriptional repression [ 25 , 26 ] .
several previous studies have shown that hkac at the insulin gene promoter was specific to  cells and islet - derived precursor cells , which was highly correlated with the recruitment of p300 [ 27 , 28 ] . in vitro studies with hdac inhibitors ( hdaci ) suggested that hkac was essential in the development of pancreas .
these findings can not fully demonstrate the underlying mechanism of dn ; in this review , we will discuss the current opinions of hac and nonhistone acetylation on inflammation , fibrosis , and oxidative stress in the development and progression of dn ( table 1 ) .
diabetic patients showed that levels of h3 acetylation at lysine 9 and 14 and h4 acetylation at lysine 5 , 8 , and 12 were increased at tnf- and cox-2 inflammatory genes promoters in human blood monocytes .
another study showed that oxidized lipids could increase h3k9/14ac at mcp-1 and il-6 gene promoters in a creb / p300-dependent manner , along with the inflammatory genes expression .
advanced dn in db / db mice underwent by uninephrectomy is specifically associated with increased acetylation of h3k9 and h3k23 .
a recent study revealed that acetylation of h3k9 , h3k18 , and h3k23 were significantly increased in the renal cortex of akita mice , hg and nab - induced h3k9 and h3k18 acetylation was elevated in the mesangial cells also , which were associated with inflammatory factors such as mcp-1 , icam-1 , vcam-1 , and inos expression linked to the development of dn .
thioredoxin - interacting protein ( txnip ) has been demonstrated to play an important role in the pathogenesis of dn .
hg - induced txnip expression was associated with the stimulation of activating h3k9ac in mcs of diverse species , which could drive the expression of proinflammatory genes predisposing to dn .
tgf-1 is established to be involved in the pathogenesis of dn , the underlying mechanism of which is still unclear .
tgf-1 treatment could increase acetylation of histone ( h3k9 , h3k14 , and h3k27 ) as well as ets-1 in mouse renal glomerular mesangial cells ; furthermore , acetylation of ets-1 and histone h3 was increased in glomeruli from diabetic db / db mice also , both of which can increase mir-192 expression contributing to dn .
tgf-1 treatment increased h3k9/14ac at the pai-1 and p21 promoters near smad and sp1 binding sites in rmcs , acetylation of smads was also increased [ 36 , 37 ] , and hg - treated rmcs exhibited increased levels of h3k9/14ac that can be blocked by tgf-1 antibodies , which played an important role in tgf-1 and hg - induced deregulated gene expression associated with hypertrophy and fibrosis linked to dn .
hg stimulation can also increase h3k9/14ac at the rage , pai-1 , and mcp-1 promoters , which can be further augmented by hg+ang ii ( hg / a ) , suggesting the key roles of h3k9/14ac in the key dn - related genes expression .
excessive h3k9/14ac levels were reported at the ctgf , pai-1 , and fn-1 promoters in diabetic kidneys , which were associated with p300/cbp activation .
although there is a conflicting result in an animal study that the level of h3k9/14ac was decreased in the stz - induced type 1 diabetic rat kidney [ 40 , 41 ] , the majority of hac is involved in the development and progression of dn . for the past few years
, the phenomenon  metabolic memory  has been implicated in the pathogenesis of diabetes and its complications such as dn .
a study of patients from dcct conventional treatment groups showed that there was association between hba1c level and h3k9ac ; hyperacetylated promoters included more than 15 genes related to the nf-b pathway and could be enriched in genes associated with diabetic complications , which may be a possible epigenetic explanation along with hkme [ 16 , 17 , 43 ] for metabolic memory phenomenon in humans .
endoplasmic reticulum stress ( ers ) is an important mechanism responsible for the pathogenesis of dn .
histone h4 acetylation levels are increased at glucose - regulated protein ( grp78 ) promoters and decreased at c / ebp - homologous protein ( chop ) promoters , which are associated with renal cell apoptosis , proteinuria , and increases of scr ; these results provide initial experimental evidences for understanding the mechanism of dn . apart from hac , nonhistone proteins acetylation can also take part in the pathogenesis of dn .
fork box o4 ( foxo4 ) transcription factor can be activated to promote podocyte apoptosis by ages through bcl2111 expression , at the same time , age - bsa can also increase foxo4 acetylation ; a recent study showed that alteration of foxo4 acetylation and downregulation of sirt1 expression in dm promote podocyte apoptosis ; foxo4 acetylation reduction could be a therapeutic potential for preventing diabetic podocyte loss .
enhanced nf-b acetylation level was present in both diabetic rats and hg - treated rmc leading to dn in another study , which can be dampened by 3,5-diiodothyronine ( t2 ) involved regulation of sirt1 ; acetylation of nf-b p65 and stat3 was increased in both mice and human diabetic kidneys and ages induced human podocytes , suggesting their critical roles in dn .
p65 acetylation was also increased by hg in rmcs , pns could protect diabetic kidney through decreasing induction of inflammatory cytokines and tgf-1 .
smad 3 acetylation has been implicated in the pathogenesis of dn recently [ 49 , 50 ] , overexpression of transcription factor srebp-1 induces glomerulosclerosis of dn ; srebp-1a k333 acetylation by cbp is required for smad3 association and srebp-1 transcriptional activity ; both smad3 and srebp-1a activation regulates tgf-1 transcriptional responses associated with dn , srebp-1 inhibition could be a novel therapeutic strategy for dn .
nephrin acetylation in diabetic podocytopathy has seldom been addressed before , a recent study showed that nephrin acetylation was reduced in stz - induced diabetic mice kidney ; increasing mir-29a may protect diabetic podocytopathy by modulating nephrin acetylation .
type a hats ( nuclear ) exist in nucleus , including ( 1 ) gnat ( gcn5 ) family such as gcn5 , p / caf , and elp3 , ( 2 ) myst ( hmof / myst1 , hbo1/myst2 , moz / myst3 , morf / myst4 , and tip60 ) family , ( 3 ) p300/cbp , ( 4 ) basal tf family ( tfiiic and taf1 ) , and ( 5 ) nrcf family , src , and actr / ncoa3 , which can acetylate nucleosomal histones and other chromatin - associated proteins , while type b hats are cytoplasmic and acetylate newly synthesized histones .
hkac is generally mediated by hats including p300 , cbp , p / caf , and tip60 , which is associated with gene activation via adding acetyl groups .
in addition , hats can also regulate gene expression through acetylation of nonhistone proteins such as smads , p53 , sp1 , and nf-b . among the studies of hats and their links with dn development , in vitro and in vivo studies showed that hats cbp and p / caf recruitment was increased under diabetic conditions , which led to upregulated hkac at inflammatory genes promoters continent with the gene expression [ 30 , 53 ] .
it was implicated that p300 played important roles in oxidative stress - induced parp and nf-b signaling in hg - treated endothelial cells and diabetic kidneys [ 5355 ] ; further study showed that hg upregulated p300 , which increased hac at promoters of key ecm protein fn , as well as vasoactive factors such as et-1 and vegf in endothelial cells .
another study showed that tgf-1 increased h3k9/14ac by recruiting the hats p300 and cbp ; tgf-1 treatment also increased association of p300 with smad2/3 and sp1 , cotransfection experiments showed that p300 and cbp , but not p / caf , upregulated transcriptional activity of pai-1 and p21 promoters and increased tgf-1-induced gene expression . on the contrary , inhibition of cbp and p300 by overexpressing dominant - negative mutants
p / caf was found sharply increased in the renal cortex of akita mice , while gcn5 was significantly decreased in the hg group , suggesting that the inflammatory genes expressions were related to dn . in vivo and in vitro results of
another report showed that p / caf was closely related to h3k18ac levels at inflammatory molecules icam-1 and mcp-1 promoters , which could be a potential therapeutic agent for inflammation - related renal diseases including dn .
all the data implied that hats have critical roles in acetylating both histones and nonhistone proteins in the pathogenesis of dn ; these results point to the necessity of further studies on the hats activity in the development of dn , which may be therapeutic targets in the future .
in preclinical trials , small - molecule hats inhibitors have been shown to sensitize cancer cells to ionizing irradiation .
curcumin , the p300/cbp inhibitor , extracted from rhizomes of turmeric curcuma longa , which was supposed to be a new target molecule for treating cns disorders and cancer [ 61 , 62 ] , was firstly reported to prevent the development of dn involved in the changes of ptms of histone h3 including acetylation and phosphorylation and the changes in hsp-27 and p38 expression in diabetic rats .
curcumin could also prevent hg - induced key ecm genes and vasoactive factors ( enos and et-1 ) expression levels associated with dn in endothelial cells ; it was able to reverse the upregulation of vasoactive factors , tgf-1 and ecm protein fn in stz - induced diabetic kidneys , which was associated with p300 and nf-b activity changes .
curcumin was also found to reverse hg - induced cytokines ( il-6 , tnf- , and mcp-1 ) production in human monocytes via epigenetic changes involving nf-b , but dietary curcumin failed to decrease albuminuria either before or after diabetes induction .
curcumin analogue , c66 , has been demonstrated to significantly and persistently prevent renal injury and dysfunction in diabetic mice via downregulation of jnk activation and consequent suppression of diabetes - related increases in p300/cbp expression and histone acetylation ( h3k9/14ac ) . in a recent study
, c646 , a novel p300/cbp specific inhibitor , has been declared to specifically suppress the growth of cbp - deficient hematopoietic and lung cancer cells in vivo and in vitro . in another in vitro study , histone h3ac activated tgf-1/smad3 pathway during emt of human peritoneal mesothelial cells ; c646 could reverse the mesenchymal phenotype transition .
c646 was also reported reversing acetylation involved in hg - induced txnip expression leading to dn .
to date , 18 hdacs have been identified in humans and divided into 4 distinct classes based on their homology to yeast hdac , in which class i ( hdac1 , 2 , 3 , and 8) , class ii including iia ( hdac4 , 5 , 7 , and 9 ) and iib ( hdac6 and 10 ) , and class iv ( hdac11 ) have structurally similar zinc - dependent active sites , whereas class iii , sirtuins ( sirts1 - 7 ) , are zinc - independent but require cofactor nicotinamide adenine dinucleotide ( nad ) .
hdacs can remove acetyl groups from conserved lysine residues and nonhistone proteins and generally act as corepressors with some exceptions .
most research related to the epigenetics of dn has focused on hac ; different classes of hdacs are involved in distinct pathways that engaged in the pathogenesis of dn .
overexpression of hdac1 and hdac5 blocked tgf-1-induced gene expression , whereas inhibition of hdacs upregulated h3k9/14ac and gene expression , further supporting the key inhibitory roles of hdacs in tgf-1-induced gene expression .
a recent study showed that hdac1 was significantly decreased in the renal cortex of akita mice , while the levels of hdac2 in akita and wt mice were unchanged , and hdac1 was significantly decreased in hg - cultured hbzy-1 cell , which can upregulate diabetes- , hg- , and nab - induced histone hyperacetylation leading to inflammatory factors elevation associated with dn .
glomerular sclerosis is also a core characteristic of dn resulting from excessive ecm deposition in the glomerular mesangium and the loss of glomerular epithelial cells , followed by aberrant fibrosis in the glomerular structure .
hdac2 activity was markedly increased in the kidneys of type 1 and type 2 murine models and tgf-1 treated nrk52-e cells , which played an important role in the development of dn .
knockdown of hdac2 in cell culture reduced ecm components accumulation , further implicating the role of hdac2 in the fibrosis .
oxidative stress is also of the view to play an important role in regulating fibrosis in dn ; a potent oxidative stress inducer h2o2 can increase hdac2 levels , which may be an underlying mechanism in the pathogenesis of dn .
hdac4 is regarded as a contributor to podocyte injury in type 1 and type 2 diabetic models and diabetic patients and could suppress autophagy related with podocyte injury in dn by deacetylating stat1 , suggesting that hdac4 is important to accelerate dn in epigenetic and nonepigenetic mechanisms [ 70 , 71 ] .
sirts have been shown to be involved in diverse cellular processes such as insulin secretion , cell cycle , and apoptosis .
dysfunction of sirt1 may contribute to abnormal cancer metabolism , cancer stemness , neurological disorders , obesity , and diabetes .
a previous study showed that decreased sirt1 level in diabetic kidney and intermittent fasting ( if ) prevents this decrease ; sirt1-dependent deacetylation is thought to mediate p53 expression and activation , which could play a renoprotective effect of if in diabetes .
another report showed that resveratrol could prevent decreased sirt1 and increased p53 expression in diabetic kidney , which could be responsible for preventing apoptosis in type 1 diabetic kidney .
resveratrol has also been demonstrated to reduce oxidative stress and maintain mitochondrial function related with sirt1 activation in hg - treated mcs and db / db diabetic mice [ 75 , 76 ] .
sirt1 in proximal tubules ( pt ) has been reported to attenuate diabetic albuminuria by suppressing the overexpression of tight junction protein claudin-1 via hypermethylation of the claudin-1 gene in podocytes [ 77 , 78 ] .
another previous report showed that sirt1 could inhibit tgf-1-induced glomerular mesangial cell apoptosis via smad7 deacetylation , and overexpression of sirt1 attenuated ros - induced apoptosis in mesangial cells through p53 deacetylation and provided a new therapeutic strategy for kidney glomerular diseases ; tsg has been proven to protect dn through inhibiting tgf-1 expression partially mediated by sirt1 activation .
conditional sirt1 deletion in podocytes of diabetic db / db mice developed more acetylation of nf-b p65 and stat3 , proteinuria , and kidney injury compared with db / db mice without sirt1 deletion , suggesting the protective roles of sirt1 in tfs acetylation on dn .
dietary restriction was reported to ameliorate dn through regulation of the autophagy via restoration of sirt1 in diabetic fa / fa rats .
the beneficial effects of sirt1 on age - associated dn correlate with the activation of nrf2/are antioxidative pathway [ 83 , 84 ] .
all the findings suggested the possibility of sirt1 as the target of treatment in dn [ 8587 ] . taken together , these studies highlight important and different roles of hdacs in the pathways , and most of them are beneficial , suggesting hdacs will be the targets for the prevention of dn despite the fact that further studies are needed .
the present hdacis include both natural and synthetic compounds and are subdivided into 5 categories : short - chain fatty acids , cyclic peptides , benzamides , electrophilic ketones , and small - molecule hydroxamic - acid - derived compounds [ 52 , 88 ] .
hdacis are regarded as potential anticancer agents and are promising for the treatment of a lot of diseases such as inflammation and neurological diseases .
recently , hdacis have been identified as a novel class of potential therapeutic agents for dn . here
we list some progress of hdacis applied in the treatment of dn regarding antifibrotic , anti - inflammatory , and antioxidative effects .
nevertheless , most of the hdacis are nonselective and target both nuclear histones and cytoplasmic nonhistone proteins .
it was found that millimolar concentrations of n - butyrate induce accumulations of acetylated histones in cells in the 1970s and inhibited deacetylation [ 72 , 90 , 91 ] .
sodium butyrate ( nab , a nonselective inhibitor of hdacs ) , a short - chain fatty acid , can upregulate hac levels , promote tumor cell senescence and apoptosis , and inhibit tumor cell proliferation .
nab was used as animal feed additive and played a major role in the treatment of neurodegenerative conditions . in vivo
, it was reported that nab could not only decrease blood glucose , creatinine , and urea but also ameliorate histological changes , fibrosis , apoptosis , and dna damage in the kidneys of juvenile diabetic rats .
saha ( suberoylanilide hydroxamic acid , vorinostat ) , a nonselective hdaci , designed and synthesized as a hybrid polar compound that can strongly induce erythroid differentiation [ 72 , 93 ] , is orally bioavailable and clinically applicable .
saha can reduce albuminuria , glomerular hypertrophy , and glomerular type iv collagen deposition through an enos - dependent mechanism , without affecting blood pressure or blood glucose concentration .
indeed , another study showed that saha attenuated early renal enlargement in stz - induced diabetic rats , which is supposed to be mediated partly through downregulating egfr .
these results indicated the key role of saha in attenuating fibrosis and oxidative damage in dn .
trichostatin a ( tsa ) , the natural product isolated from a streptomyces strain , originally identified as an antifungal antibiotic , was discovered to have potent hdac inhibition activity in 1990 .
tsa was reported to act as an agent in preventing dn in diabetic rats , by blocking tgf-1-induced ecm accumulation   and emt in diabetic kidneys   as well as in renal epithelial cells ; knockdown of hdac2 had similar effect of tsa treatment mediated by ros .
valproic acid ( vpa ) , a broad - spectrum hdaci , is a first - line drug used for the treatment of epilepsy and migraine .
vpa treatment alleviated renal injury and fibrosis in stz - induced diabetic kidney by preventing myofibroblast activation and fibrogenesis through hdac4/5/7 inhibition in a dose - dependent manner , vpa has also been proven to ameliorate the podocyte and renal injuries by facilitating autophagy and inactivation of nf-b / inos pathway .
a recent study showed that vpa can attenuate renal injury in a rat model of dn , by upregulating the histone h4 acetylation levels at the promoter of grp78 and downregulating the histone h4 acetylation at the promoter of chop . to our knowledge , at the time of the present review , the molecular implications of hdacis were identified in the treatment of dn , and the development of selective hdacis in preventing dn may be part of the most prevalent areas in the drug discovery .
recent research has concentrated on histone modifications to provide a reliable theoretical basis for clinical treatment . a comprehensive understanding of hac mechanisms can give rise of novel therapeutic options for dn .
increasing in vitro and in vivo evidences implicated that reversible histone and nonhistone acetylation play important roles in the pathogenesis of dn , suggesting that hac regulation could be promising therapeutic targets for dn .
hats and a small number of hdacs provide a central mechanism for regulating gene expression and cellular signaling events in dn ( table 2 ) .
experimental evidences suggest that hats / hdacs inhibitors and a large number of hdacs can delay the development and progression of dn ( tables 2 and 3 ) .
hats inhibitor curcumin and its analogue c66 could protect renal injuries in diabetic patients and diabetic animal models ; apelin-13 and esculetin treatment could be innovative therapeutic agents for dn via regulation of hac also [ 33 , 40 , 41 ] .
continued research is needed to better understand the roles of hac in the process of dn , the modifiers and the mechanism that regulate them , and address the curative potential of more selective hats inhibitors and hdaci in treating dn .
 diabetic nephropathy ( dn ) remains a leading cause of mortality worldwide despite advances in its prevention and management . 
 a comprehensive understanding of factors contributing to dn is required to develop more effective therapeutic options . 
 it is becoming more evident that histone acetylation ( hac ) , as one of the epigenetic mechanisms , is thought to be associated with the etiology of diabetic vascular complications such as diabetic retinopathy ( dr ) , diabetic cardiomyopathy ( dcm ) , and dn . 
 histone acetylases ( hats ) and histone deacetylases ( hdacs ) are the well - known regulators of reversible acetylation in the amino - terminal domains of histone and nonhistone proteins . in dn , however , the roles of histone acetylation ( hac ) and these enzymes are still controversial . 
 some new evidence has revealed that hats and hdacs inhibitors are renoprotective in cellular and animal models of dn , while , on the other hand , upregulation of hac has been implicated in the pathogenesis of dn . in this review , 
 we focus on the recent advances on the roles of hac and their covalent enzymes in the development and progression of dn in certain cellular processes including fibrosis , inflammation , hypertrophy , and oxidative stress and discuss how targeting these enzymes and their inhibitors can ultimately lead to the therapeutic approaches for treating dn . 