ReviewArticle Epigenetic Regulations in Diabetic Nephropathydownloads.hindawi.com/journals/jdr/2017/7805058.pdf · 4 JournalofDiabetesResearch monitoring of diabetic patients. On

Review ArticleEpigenetic Regulations in Diabetic Nephropathy

Zeyuan Lu1 Na Liu2 and FengWang1

1Department of Nephrology Shanghai Jiao Tong University Affiliated Sixth Peoplersquos Hospital Shanghai China2Department of Nephrology Shanghai East Hospital Tongji University School of Medicine Shanghai China

Correspondence should be addressed to Na Liu naliubrown163com and Feng Wang zyzwq1030163com

Received 1 December 2016 Revised 6 February 2017 Accepted 9 February 2017 Published 19 March 2017

Academic Editor Hiroshi Okamoto

Copyright copy 2017 Zeyuan Lu et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Diabetic nephropathy (DN) is a chronic complication of diabetes and the most common cause of end-stage kidney disease Ithas been reported that multiple factors are involved in the pathogenesis of DN while the molecular mechanisms that lead to DNare still not fully understood Numerous risk factors for the development of diabetic nephropathy have been proposed includingethnicity and inherited genetic differences Recently with the development of high-throughput technologies there is emergingevidence that suggests the important role of epigenetic mechanisms in the pathogenesis of DN Epigenetic regulations includingDNA methylation noncoding RNAs and histone modifications play a pivotal role in DN pathogenesis by a second layer of generegulation All these findings can contribute to developing novel therapies for DN

1 Introduction

Diabetic nephropathy (DN) is characterized by glomerularhypertrophy proteinuria decreased glomerular filtrationand renal fibrosis resulting in the loss of renal function DN isa major complication associated with both type 1 and type 2diabetes [1]More than 12 of patients with type 2 diabetes and13 of those with type 1 diabetes develop kidney disease andDN is a prime reason for dialysis inmany developed countries[2] DN is classified as a small blood vessel complication ofdiabetes Both ethnicity and inherited genetic differences areproposed for response to the development of DN [3 4] Intra-glomerular hypertension and hyperfiltration are triggeredbecause of the hyperglycemia insulin resistance and aberranthemodynamicsHowever themolecularmechanisms leadingto DN are still not fully understood Recently there is emerg-ing evidence that suggests the important role of epigeneticmechanisms in the pathogenesis of DN It is rather remark-able that individuals who are exposed to hyperglycemia morelikely develop diabetic complications This phenomenon isreferred to as metabolic memory or the legacy effect [5]

Epigenetics refers to heritable patterns of gene expressionthat are not dependent on the DNA sequence informationIt has been studied in a variety of organisms [3] The epi-genetic modifications include cytosine methylation of DNA

(DNA methylation) histone posttranslational modifications(PTMs) and noncoding RNAs [6] The most well-knownand best-characterized epigenetics are DNA methylationwhich converts the DNA nucleotide cytosine into 5-methyl-cytosine Another important epigeneticmark is themodifica-tion of histone proteins around which less than two turns ofDNA are wound to form the nucleosome Besides noncodingRNA is regarded as an important part of epigenetic which canregulate gene expression at both transcription and translationlevel [7] Numerous studies have shown that epigenetic pro-cesses are involved in the pathogenesis of DN In this reviewwe discuss recent advances in the epigenetics of DN includ-ing DNA methylation noncoding RNA and histone modifi-cations with the focus on the role of three types of epigeneticmodification in DN

2 DNA Methylation in DN

DNA methylation frequently described as a ldquosilencingrdquoepigenetic mark usually occurs at 51015840-cytosines of CpG dinu-cleotide and is catalyzed by specific DNA methyltransferases[8] Generally if DNA methylation exists at gene promoterregions it will lead to gene repression On the other handif DNA methylation exists at gene bodies it can modulatetranscription elongation and alternative splicing One of

HindawiJournal of Diabetes ResearchVolume 2017 Article ID 7805058 6 pageshttpsdoiorg10115520177805058

2 Journal of Diabetes Research

the mechanisms of DNA methylation is inhibiting geneexpression by methyl binding proteins which can recruittranscriptional corepressors Besides another mechanism isthat it can interfere with the binding of transcription factorsat promoters [7]

Hyperglycemia has been reported to changeDNAmethy-lation Moreover in the kidney proximal tubules diabetesis induced aberrant DNA methylation [9 10] Howeverelevated glucose level is not the only reason for maladaptiveepigenetic modifications in diabetes Many other factors canmodify epigenetic profiles such as hypoxia inflammationand cytokines [11 12]The role ofDNAmethylation inDNhasdrawnmore attention partly because of the application of high-throughput sequencing technologies By comparing type 2diabetes patients with or withoutDN several genes have cleardifferential methylation The gene UNC13B is one of themwhich has been suggested tomediate apoptosis in glomerularcells as a result of hyperglycaemia and could be relevant tothe initiation and pathogenesis of DN [13] Another teamidentified 187 gene targets that showdifferentially site-specificDNA methylation in DNA extracted from the saliva ofpatients with type 2 diabetes and end-stage kidney disease(ESRD) when compared to diabetic patients without ESRD[14] In microdissected tubules obtained from patients withDN DNA methylation profiles demonstrated differentiallymethylated genes implicated in fibrogenesis [15] Anotherstudy analyzed DNAmethylation in kidney tubular epithelialcells and showed significance differences of methylation in1061 genes in DN patients compared to controls [16]

Involvement ofDNAmethylation inDN is also supportedby experimental studies It is reported that hypermethylationof RASAL1 increased Ras activation in fibroblasts leading toproliferation and fibrosis [17] Exposure of vascular endothe-lial cells to hyperglycemia led to changes inDNAmethylationat several genes involved in endothelial cell dysfunction [18]Taken together these researches have identified the gene tar-gets for DN and also prove the importance of DNAmethyla-tion in regulating fibrotic and other genes associated withDN

3 Noncoding RNAs in DN

RNA used to be considered as an intermediate moleculein protein synthesis which is no more than a template forprotein synthesis However with the development of high-throughput platforms the classical view of the molecularbiology has changed [19 20] It has been reported that lessthan 2 of human genome is transcribed into RNA tran-scripts that can code protein [21ndash23] It means that most ofRNAs are noncoding RNAs (ncRNAs) separated into longncRNAs (more than 200 nucleotides in length) and smallncRNAs (less than 200 nucleotides)

4 miRNA

MicroRNAs (miRNAs) are small noncoding RNA moleculescapable of silencing mRNA targets miRNAs contain 20sim22nucleotides and typically bind to the 31015840 untranslated regionsof target mRNA to promote translational repression andor

mRNA degradation [24] It is reported that more than 2500mature miRNAs are identified in humans and regulated atleast 60 of protein-coding genes [25] Hence miRNAs canmodulate the expression of numerous genes to alter key cel-lular functions and influence the course of various diseasesSomemiRNAs are considered to have renal functions becausethey are enriched in kidney only [26] Besides miRNAs mayhave cell type and tissue-specific functions since differentmiRNA expression patterns were found in renal cortex andmedulla [27]

Many miRNAs involved in DN have been identified [28]Compared with nondiabetic control mice several miRNAs(miR192 miR-200bc miR21 and miR-1207-5p) are upreg-ulated in TGF-1205731-treated murine mesangial cells and inrenal glomeruli of mouse models of diabetes The TGF-1205731pathway is a master regulator of renal fibrosis which playsan important role in DN Among these miRNAs the best-studied one is miR-192 which has a conflicting expression inDNmiR-192 was reported to be upregulated in the glomeruliof streptozotocin- (STZ-) induced and dbdb diabetic mice[29]The upregulation of miR-192 expression is also shown intubular cells treatedwith TGF-1205731 [30]However other groupsfound a reduction in miR-192 in diabetic Apoeminusminus micewhich was associated with increased fibrosis [31 32] Investi-gation results explained that these complexities are due to celltype-specific effects of miRNA and differences in the animalmodels studied [33] while considering that decreasing ofmiR-192 is not pathogenic because Kato et al demonstratedthat miR-192 knockout (KO) mice had no kidney problemand milder kidney injury under diabetes Moreover somestudies had reported that the decreasing of miR-192 at laterstage can be just a result of nonspecific degradation of RNAsin progression of DN but not pathogenic [34 35] It hasreported that the level of miR-192 is increased in the earlystage of DN which can be prevented via suppressing thismicroRNA expression in the mice model of DN [36 37]Many articles describe the function of miR-192 in DN FirstmiR-192 can lead to upregulation of Col1a2 and Col4a1in mesangial cells They are key genes associated with thepathogenesis of DN [29] Second miR-192 can also regulateothermiRNAs such asmiR-216amiR-217 andmiR-200bc Itis known thatmiR-200 familymembers can regulate Zeb1 andZeb2MiR-200 can regulate collagen expression and promotethe autoregulation of TGF-1205731 in murine mesangial cells byinhibiting Zeb1 Moreover miR-216miR-217 also related toTGF-1205731-induced Akt activation and cellular hypertrophywhich are considered to be a pivotal feature ofDN [38]ThirdmiR-192 is reported to have an amplification loop with p53 inresponse to TGF-1205731 In this study the levels of TGF-1205731 p53and miR192 were all increased in the renal cortex of diabeticmice compared with control ones [34] Generally miR-192 isone of the major regulators in the pathologic mechanism ofDN

Similarly miR-21 is known to modulate the expressionand activities of important factors related to diabetic kidneydisease The mechanism of miR-21 regulating renal injuryis targeting Smad7 because downregulation of miR-21 canrestore Smad7 levels and suppressed activation of the TGF-120573 and NF-120581B signaling pathway [39] In the renal cortex of

Journal of Diabetes Research 3

OVE26 type 1 diabetic mice miR-21 was upregulated andcould target Pten and promote mTOR activation which isrelated to DN

5 lncRNA

Long noncoding RNAs are defined as a large and diversegroup of non-protein-coding transcripts longer than 200nucleotides [40] Based on the association with nearbyprotein-coding genes the lncRNAs can be separated into sixgroups sense (overlapping a protein-coding gene) antisense(located in antisense orientation to a protein-coding gene)bidirectional promoter (transcribed within 1 kb of promotersantisense to the protein-coding transcript) intronic (tran-scribed from an intron of a protein-coding gene) intergenic(between two protein-coding transcripts) and enhancer(transcribed from an enhancer region of a protein-codinggene) [41] Circular RNAs also have been identified as theyform covalently enclosed circular structure which usuallycome from splicing of a protein-coding gene [42] Accordingto themechanism of lncRNAs they can be classified into fourcategoriesmdashsignal decoy guide and scaffold [43] Accumu-lating evidence has demonstrated that the noncoding RNA(ncRNA) affects transcription pre-mRNA processing andtranslation [43 44]

Unlike microRNA there are only a few reports that haveshown the relationship of lncRNAs with DN First as a hostgene ncRNA RP23 together with miR-216 and miR-217 wereinduced byTGF-1205731 [45] Another host gene ncRNACJ241444can be coregulated with miR-192 and is induced by TGF-1205731 This mechanism involved the Smad transcription factorsproteinC-ets-1 and histone acetylation [46] Gene set enrich-ment analyses (GSEA) show that a megacluster of nearly40 microRNAs and their host long noncoding RNA tran-script (lnc-MGC) are coordinately increased in the glomeruliof mouse models of DN Inhibition of the host lncRNAdecreased the expression of the cluster miRNAs and attenu-ated early features ofDN in vitro inmesangial cells and in vivoinmice [47] Second another study reported that 21 commonlncRNAs were upregulated in wild-type but downregulatedin Smad3 knockout kidneys in both disease models in whichprogressive renal inflammation and fibrosis were abolishedwhen the Smad3 gene was deleted or suppressed [48] Anunbiased RNA-sequencing (RNA-seq) analysis of kidneyglomeruli identified that lncRNA Tug1 are considered as adifferentially expressed lncRNA in the diabetic milieu ThisTug1 gene is shown to regulate mitochondrial bioenergeticsin diabetic nephropathy [49] Third one lncRNA namedMalat1 may have relationship with DN It was first identifiedas a prognostic marker of survival in early-stage non-small-cell lung cancers However the expression of Malat1 is notrestricted to cancer cell and it is ubiquitously expressed inmany normal cells and tissues [50] Diabetes is usually recog-nized as the vascular disease characterized by vasoregulationchange increased generation of reactive oxygen intermedi-ates inflammatory activation and altered barrier function[51] It has been reported that the MALAT1 level is signif-icantly upregulated in diabetic animal models MoreoverMALAT1 expression is upregulated in the kidneys of diabetic

mice The mechanism of the result is lncRNA MALAT1inhibition attenuates the inflammatory response in conditionof hyperglycaemia via serum amyloid antigen3 (SAA3) [52]Generally the relationship of lncRNA and DN seems anexciting emerging field that is expected to havemore findings

6 Histone Modifications in DN

Histone posttranslational modifications (PTMs) regulategene expression chromatin structure Important PTMs ofhistone include lysine acetylation (Kac) lysine methylation(Kme) and phosphorylationThey are mostly in the exposedamino-terminal tails [53] Histone Kac is catalyzed by his-tone acetyltransferases such as p300 and CBP which alsoact as transcription coactivators Lysine is deacetylated byHDACs Kme is carried out by lysine methyl transferases anddemethylation by lysine demethylases [54]

Recently some papers have shown the role of histonemodifications in diabetes and diabetic complications includ-ing DNHistone PTMs are among the best-characterized epi-genetic modifications with respect to diabetes and are clearlyimplicated in the reduction in the expression of genes impli-cated in DN [55] The role of histone PTMs in DN has beeninvestigated in vitro and in vivoThe functional role of histoneH3 lysine methylation (H3Kme) in TGF-1205731-mediated extra-cellular matrix (ECM) gene expression in mesangial cells hasbeen shown under normal and high-glucose (HG) conditions[56] Another study reported that high glucose inhibitedDNA methylation and increased H3K9ac at the promoterof the redox regulating protein p66 and upregulated p66shcexpression in diabetic murine kidney [57] Histone modi-fications also showed connection with microRNA Histoneacetylation by p300 activated by Akt is involved in inductionof miR-192 in diabetic nephropathy These findings provideinsight into the regulation of miRNAs through signaling-mediated changes in epigenetic histone acetylation undernormal and disease states [46]

7 Epigenetic and ncRNA-Based Therapy

As the leading cause of renal failure DN requires renalreplacement therapy worldwide However effective meth-ods to identify and halt progression of pathophysiologicalchanges of DN remain elusive [58 59] In the past protein-uria renal pathology and renal function are major diagnosisfor DN Recently with the development of new technologiessuch as quantitative real-time PCR microarray and high-throughput sequencing it is possible for us to use ncRNA asthe biomarker for DN NcRNAs have their own characteris-tics Firstly miRNAs have consistency in particular diseaseand have tissue specificity Secondly miRNAs are highlyexpressed in urine and have stability storage in tissue [60 61]Thirdly in some casesmiRNAchanges expression level in theearly stage of DN which related to fibrosis [62] For exampleMohan et al reported thatmiR-451-5p andmiR-16 in diabetesappeared to be protective against diabetes-induced kidneyfibrosis while UE miR-451-5p may hold prognostic value asan early and sensitive noninvasive indicator of renal disease[63] Similar to miRNA lncRNA also can help in serial


monitoring of diabetic patients On the other hand thereare some disadvantages of using ncRNA as biomarkers todiagnose DN With developing of renal failure low miRNAlevel may be due to decreasing of synthesis capacity So itcannot be attributed to downregulated expression

The current standard therapy of diabetic nephropathyinvolves intensive treatment of hyperglycemia and strictblood pressure control mainly via blockade of the renin-angiotensin system (RAS) [64] As discussed earlier in thisreview epigenetic regulation of DNA and histones playsimportant parts in DN It has been reported that histonemethylation has connection with metabolic memory Pre-liminary work in endothelial cells has shown that transientepisodes of hyperglycemia can induce changes in geneexpression that are dependent on histone modifications andthat these changes persist after return to normoglycemia[65] Attention has been drawn to additional beneficial effectsof epigenetic modifications In connection with abnormalexpression of miRNA in DN targeting regulation of miRNAexpression is regarded as a novel therapy for DN treatment

8 Conclusions

The pathogenesis of DN involves complicated interactionsbetween metabolic and hemodynamic factors Increasingevidence suggests a critical role for epigenetic modificationsin DN In this review we have highlighted some emergingmechanisms including DNA methylation noncoding RNAand histone modification Rapid developments of high-throughput genome-wide screening techniques have greatlybroadened the understanding of genetic and epigeneticchanges in DN Unlike genetic changes epigenetic changesare reversible which means it gives an opportunity fortherapeutic development However the mechanism of actionof these inhibitors is not fully clear and more work is neededbefore understanding it Epigenetic therapy has been expectedto obtain more achievements in the future Further work inthis field of research has a chance to make a distinguishedinfluence on the therapy of DN

Competing Interests

The authors declare that they have no competing interests

Acknowledgments

This study was supported by the National Nature ScienceFoundation of China grants (81570603 to Feng Wang81670690 81470991 and 81200492 to Na Liu) Shanghai tal-ents development fund and Shanghai Pujiang Talent Projects(15PJ1406700 to Feng Wang)

References

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[2] M CThomas M Brownlee K Susztak et al ldquoDiabetic kidneydiseaserdquoNature ReviewsDisease Primers vol 1 Article ID 150182015

[3] F Regele K Jelencsics D Shiffman et al ldquoGenome-widestudies to identify risk factors for kidney disease with a focuson patients with diabetesrdquoNephrology Dialysis Transplantationvol 30 no s4 pp iv26ndashiv34 2015

[4] C C Cowie F K Port R A Wolfe P J Savage P P Molland VM Hawthorne ldquoDisparities in incidence of diabetic end-stage renal disease according to race and type of diabetesrdquo NewEngland Journal ofMedicine vol 321 no 16 pp 1074ndash1079 1989

[5] L Pirola A Balcerczyk J Okabe and A El-Osta ldquoEpigeneticphenomena linked to diabetic complicationsrdquo Nature ReviewsEndocrinology vol 6 no 12 pp 665ndash675 2010

[6] A Portela and M Esteller ldquoEpigenetic modifications andhuman diseaserdquo Nature Biotechnology vol 28 no 10 pp 1057ndash1068 2010

[7] M C Thomas ldquoEpigenetic mechanisms in diabetic kidneydiseaserdquo Current Diabetes Reports vol 16 article 31 2016

[8] P A Jones ldquoFunctions of DNAmethylation islands start sitesgene bodies and beyondrdquo Nature Reviews Genetics vol 13 no7 pp 484ndash492 2012

[9] R BarresM EOsler J Yan et al ldquoNon-CpGmethylation of thePGC-1120572 promoter through DNMT3B controls mitochondrialdensityrdquo Cell Metabolism vol 10 no 3 pp 189ndash198 2009

[10] T Marumo S Yagi W Kawarazaki et al ldquoDiabetes inducesaberrant DNA methylation in the proximal tubules of thekidneyrdquo Journal of the American Society of Nephrology vol 26no 10 pp 2388ndash2397 2015

[11] S Horsburgh P Robson-Ansley R Adams and C SmithldquoExercise and inflammation-related epigenetic modificationsfocus on DNA methylationrdquo Exercise Immunology Review vol21 pp 26ndash41 2015

[12] F I Milagro M L Mansego C De Miguel and J AMartınez ldquoDietary factors epigenetic modifications and obe-sity outcomes progresses and perspectivesrdquo Molecular Aspectsof Medicine vol 34 no 4 pp 782ndash812 2013

[13] C G Bell A E Teschendorff V K Rakyan A P MaxwellS Beck and D A Savage ldquoGenome-wide DNA methylationanalysis for diabetic nephropathy in type 1 diabetes mellitusrdquoBMCMedical Genomics vol 3 article 33 2010

[14] C Sapienza J Lee J Powell et al ldquoDNA methylation profilingidentifies epigenetic differences between diabetes patients withESRD and diabetes patients without nephropathyrdquo Epigeneticsvol 6 no 1 pp 20ndash28 2011

[15] K Hasegawa S Wakino P Simic et al ldquoRenal tubular sirt1attenuates diabetic albuminuria by epigenetically suppressingclaudin-1 overexpression in podocytesrdquo Nature Medicine vol19 no 11 pp 1496ndash1504 2013

[16] Y-A Ko D Mohtat M Suzuki et al ldquoCytosine methylationchanges in enhancer regions of core pro-fibrotic genes charac-terize kidney fibrosis developmentrdquoGenome Biology vol 14 no10 article R108 2013

[17] W Bechtel S McGoohan E M Zeisberg et al ldquoMethylationdetermines fibroblast activation and fibrogenesis in the kidneyrdquoNature Medicine vol 16 no 5 pp 544ndash550 2010

[18] L Pirola A Balcerczyk R W Tothill et al ldquoGenome-wideanalysis distinguishes hyperglycemia regulated epigenetic sig-natures of primary vascular cellsrdquo Genome Research vol 21 no10 pp 1601ndash1615 2011


[19] F Liang I Holt G Pertea S Karamycheva S L Salzberg andJ Quackenbush ldquoGene index analysis of the human genomeestimates approximately 120000 genesrdquo Nature Genetics vol25 no 2 pp 239ndash240 2000

[20] P Kapranov S E Cawley J Drenkow et al ldquoLarge-scaletranscriptional activity in chromosomes 21 and 22rdquo Science vol296 no 5569 pp 916ndash919 2002

[21] S Djebali C A Davis AMerkel et al ldquoLandscape of transcrip-tion in human cellsrdquo Nature vol 489 pp 101ndash108 2012

[22] Consortium Encode Project ldquoAn integrated encyclopedia ofDNA elements in the human genomerdquo Nature vol 489 pp 57ndash74 2012

[23] Y Okazaki M Furuno T Kasukawa et al ldquoAnalysis of themouse transcriptome based on functional annotation of 60770full-length cDNAsrdquo Nature vol 420 pp 563ndash573 2002

[24] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[25] A Kozomara and S Griffiths-Jones ldquomiRBase annotating highconfidence microRNAs using deep sequencing datardquo NucleicAcids Research vol 42 no 1 pp D68ndashD73 2014

[26] Y Sun S Koo N White et al ldquoDevelopment of a micro-arrayto detect human and mouse microRNAs and characterizationof expression in human organsrdquo Nucleic acids research vol 32no 22 article e188 2004

[27] Z Tian A S Greene J L Pietrusz I R Matus and MLiang ldquoMicroRNA-target pairs in the rat kidney identified bymicroRNAmicroarray proteomic and bioinformatic analysisrdquoGenome Research vol 18 no 3 pp 404ndash411 2008

[28] H Wu L Kong S Zhou et al ldquoThe role of microRNAs indiabetic nephropathyrdquo Journal of Diabetes Research vol 2014Article ID 920134 12 pages 2014

[29] M Kato J Zhang M Wang et al ldquoMicroRNA-192 in diabetickidney glomeruli and its function in TGF-120573-induced collagenexpression via inhibition of E-box repressorsrdquo Proceedings of theNational Academy of Sciences of theUnited States of America vol104 no 9 pp 3432ndash3437 2007

[30] A C K Chung X R Huang X Meng and H Y Lan ldquomiR-192mediates TGF-120573Smad3-driven renal fibrosisrdquo Journal of theAmerican Society of Nephrology vol 21 no 8 pp 1317ndash13252010

[31] A Krupa R Jenkins D DongLuo A Lewis A Phillipsand D Fraser ldquoLoss of microRNA-192 promotes fibrogenesisin diabetic nephropathyrdquo Journal of the American Society ofNephrology vol 21 no 3 pp 438ndash447 2010

[32] B Wang M Herman-Edelstein P Koh et al ldquoE-cadherinexpression is regulated by miR-192215 by a mechanism that isindependent of the profibrotic effects of transforming growthfactor-120573rdquo Diabetes vol 59 no 7 pp 1794ndash1802 2010

[33] M Kato and R Natarajan ldquoDiabetic nephropathy-emergingepigeneticmechanismsrdquoNature Reviews Nephrology vol 10 no9 pp 517ndash530 2014

[34] SDDeshpande S PuttaMWang et al ldquoTransforming growthfactor-120573-induced cross talk between p53 and aMicroRNA in thepathogenesis of diabetic nephropathyrdquo Diabetes vol 62 no 9pp 3151ndash3162 2013

[35] M Kato and R Natarajan ldquoMicroRNAs in diabetic nephropa-thy Functions biomarkers and therapeutic targetsrdquo Annals ofthe New York Academy of Sciences vol 1353 pp 72ndash88 2015

[36] S Putta L Lanting G Sun G Lawson M Kato and RNatarajan ldquoInhibiting microRNA-192 ameliorates renal fibrosisin diabetic nephropathyrdquo Journal of the American Society ofNephrology vol 23 no 3 pp 458ndash469 2012

[37] Y Jia M Guan Z Zheng et al ldquoMiRNAs in urine extracellularvesicles as predictors of early-stage diabetic nephropathyrdquoJournal of Diabetes Research vol 2016 Article ID 7932765 10pages 2016

[38] M Kato L Arce M Wang S Putta L Lanting and RNatarajan ldquoA microRNA circuit mediates transforming growthfactor-1205731 autoregulation in renal glomerular mesangial cellsrdquoKidney International vol 80 no 4 pp 358ndash368 2011

[39] X Zhong A C K Chung H Y Chen et al ldquoMiR-21 is a keytherapeutic target for renal injury in a mouse model of type 2diabetesrdquo Diabetologia vol 56 no 3 pp 663ndash674 2013

[40] J L Rinn and H Y Chang ldquoGenome regulation by longnoncoding RNAsrdquo Annual Review of Biochemistry vol 81 pp145ndash166 2012

[41] C P Ponting P L Oliver andWReik ldquoEvolution and functionsof longnoncodingRNAsrdquoCell vol 136 no 4 pp 629ndash641 2009

[42] M S Ebert and P A Sharp ldquoEmerging roles for naturalmicroRNA spongesrdquo Current Biology vol 20 no 19 pp R858ndashR861 2010

[43] K C Wang and H Y Chang ldquoMolecular mechanisms of longnoncoding RNAsrdquo Molecular Cell vol 43 no 6 pp 904ndash9142011

[44] I Ulitsky and D P Bartel ldquoXLincRNAs genomics evolutionand mechanismsrdquo Cell vol 154 no 1 pp 26ndash46 2013

[45] M Kato S Putta M Wang et al ldquoTGF-120573 activates Akt kinasethrough a microRNA-dependent amplifying circuit targetingPTENrdquo Nature Cell Biology vol 11 no 7 pp 881ndash889 2009

[46] M Kato V Dang M Wang et al ldquoTGF-120573 induces acetylationof chromatin and of Ets-1 to alleviate repression of miR-192 indiabetic nephropathyrdquo Science Signaling vol 6 no 278 articleno ra43 2013

[47] M Kato M Wang Z Chen et al ldquoAn endoplasmic reticulumstress-regulated lncRNA hosting a microRNA megaclusterinduces early features of diabetic nephropathyrdquoNature Commu-nications vol 7 article 12864 2016

[48] Q Zhou A C K Chung X R Huang Y Dong X Yu and HY Lan ldquoIdentification of novel long noncoding rnas associatedwith TGF-120573Smad3-mediated renal inflammation and fibrosisby RNA sequencingrdquo American Journal of Pathology vol 184no 2 pp 409ndash417 2014

[49] J Long S S Badal Z Ye et al ldquoLong noncoding RNA Tug1regulatesmitochondrial bioenergetics in diabetic nephropathyrdquoJournal of Clinical Investigation vol 126 no 11 pp 4205ndash42182016

[50] P Ji S Diederichs W Wang et al ldquoMALAT-1 a novel noncod-ing RNA and thymosin 1205734 predict metastasis and survival inearly-stage non-small cell lung cancerrdquo Oncogene vol 22 no39 pp 8031ndash8041 2003

[51] J-Y Liu J Yao X-M Li et al ldquoPathogenic role of lncRNA-MALAT1 in endothelial cell dysfunction in diabetes mellitusrdquoCell Death and Disease vol 5 Article ID e1506 2014

[52] P Puthanveetil S Chen B Feng A Gautam and SChakrabarti ldquoLong non-coding RNA MALAT1 regulateshyperglycaemia induced inflammatory process in the endothe-lial cellsrdquo Journal of Cellular andMolecularMedicine vol 19 no6 pp 1418ndash1425 2015

[53] T Kouzarides ldquoChromatin modifications and their functionrdquoCell vol 128 no 4 pp 693ndash705 2007

[54] R Liu K Lee and J CHe ldquoGenetics and epigenetics of diabeticnephropathyrdquo Kidney Diseases vol 1 no 1 pp 42ndash51 2015


[55] A El-Osta D Brasacchio D Yao et al ldquoTransient highglucose causes persistent epigenetic changes and altered geneexpression during subsequent normoglycemiardquo The Journal ofExperimental Medicine vol 205 pp 2409ndash2417 2008

[56] G Sun M A Reddy H Yuan L Lanting M Kato and RNatarajan ldquoEpigenetic histone methylation modulates fibroticgene expressionrdquo Journal of the American Society of Nephrologyvol 21 no 12 pp 2069ndash2080 2010

[57] F Bock K Shahzad H Wang et al ldquoActivated protein Cameliorates diabetic nephropathy by epigenetically inhibitingthe redox enzyme p66Shcrdquo Proceedings of the National Academyof Sciences of the United States of America vol 110 no 2 pp648ndash653 2013

[58] V Jha G Garcia-Garcia K Iseki et al ldquoChronic kidney diseaseglobal dimension and perspectivesrdquo The Lancet vol 382 no9888 pp 260ndash272 2013

[59] K Simpson AWonnacott D J Fraser and T Bowen ldquoMicroR-NAs in diabetic nephropathy from biomarkers to therapyrdquoCurrent Diabetes Reports vol 16 no 3 article no 35 2016

[60] MMraz KMalinova J Mayer and S Pospisilova ldquoMicroRNAisolation and stability in stored RNA samplesrdquo Biochemical andBiophysical Research Communications vol 390 no 1 pp 1ndash42009

[61] C Argyropoulos K Wang J Bernardo et al ldquoUrinaryMicroRNA profiling predicts the development of microalbu-minuria in patients with Type 1 diabetesrdquo Journal of ClinicalMedicine vol 4 no 7 pp 1498ndash1517 2015

[62] J Y Lai J Luo C OrsquoConnor et al ldquoMicroRNA-21 in glomerularinjuryrdquo Journal of the American Society of Nephrology vol 26no 4 pp 805ndash816 2015

[63] A Mohan R S Singh M Kumari et al ldquoUrinary exosomalmicroRNA-451-5p is a potential early biomarker of diabeticnephropathy in ratsrdquo PLoS ONE vol 11 no 4 Article IDe0154055 2016

[64] E Dounousi A Duni K Leivaditis V Vaios T Eleftheriadisand V Liakopoulos ldquoImprovements in the management ofdiabetic nephropathyrdquoReview ofDiabetic Studies vol 12 no 1-2pp 119ndash133 2015

[65] S Tonna A El-Osta M E Cooper and C Tikellis ldquoMetabolicmemory and diabetic nephropathy potential role for epigeneticmechanismsrdquoNature Reviews Nephrology vol 6 no 6 pp 332ndash341 2010

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Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


the mechanisms of DNA methylation is inhibiting geneexpression by methyl binding proteins which can recruittranscriptional corepressors Besides another mechanism isthat it can interfere with the binding of transcription factorsat promoters [7]

Hyperglycemia has been reported to changeDNAmethy-lation Moreover in the kidney proximal tubules diabetesis induced aberrant DNA methylation [9 10] Howeverelevated glucose level is not the only reason for maladaptiveepigenetic modifications in diabetes Many other factors canmodify epigenetic profiles such as hypoxia inflammationand cytokines [11 12]The role ofDNAmethylation inDNhasdrawnmore attention partly because of the application of high-throughput sequencing technologies By comparing type 2diabetes patients with or withoutDN several genes have cleardifferential methylation The gene UNC13B is one of themwhich has been suggested tomediate apoptosis in glomerularcells as a result of hyperglycaemia and could be relevant tothe initiation and pathogenesis of DN [13] Another teamidentified 187 gene targets that showdifferentially site-specificDNA methylation in DNA extracted from the saliva ofpatients with type 2 diabetes and end-stage kidney disease(ESRD) when compared to diabetic patients without ESRD[14] In microdissected tubules obtained from patients withDN DNA methylation profiles demonstrated differentiallymethylated genes implicated in fibrogenesis [15] Anotherstudy analyzed DNAmethylation in kidney tubular epithelialcells and showed significance differences of methylation in1061 genes in DN patients compared to controls [16]

Involvement ofDNAmethylation inDN is also supportedby experimental studies It is reported that hypermethylationof RASAL1 increased Ras activation in fibroblasts leading toproliferation and fibrosis [17] Exposure of vascular endothe-lial cells to hyperglycemia led to changes inDNAmethylationat several genes involved in endothelial cell dysfunction [18]Taken together these researches have identified the gene tar-gets for DN and also prove the importance of DNAmethyla-tion in regulating fibrotic and other genes associated withDN

3 Noncoding RNAs in DN

RNA used to be considered as an intermediate moleculein protein synthesis which is no more than a template forprotein synthesis However with the development of high-throughput platforms the classical view of the molecularbiology has changed [19 20] It has been reported that lessthan 2 of human genome is transcribed into RNA tran-scripts that can code protein [21ndash23] It means that most ofRNAs are noncoding RNAs (ncRNAs) separated into longncRNAs (more than 200 nucleotides in length) and smallncRNAs (less than 200 nucleotides)

4 miRNA

MicroRNAs (miRNAs) are small noncoding RNA moleculescapable of silencing mRNA targets miRNAs contain 20sim22nucleotides and typically bind to the 31015840 untranslated regionsof target mRNA to promote translational repression andor

mRNA degradation [24] It is reported that more than 2500mature miRNAs are identified in humans and regulated atleast 60 of protein-coding genes [25] Hence miRNAs canmodulate the expression of numerous genes to alter key cel-lular functions and influence the course of various diseasesSomemiRNAs are considered to have renal functions becausethey are enriched in kidney only [26] Besides miRNAs mayhave cell type and tissue-specific functions since differentmiRNA expression patterns were found in renal cortex andmedulla [27]

Many miRNAs involved in DN have been identified [28]Compared with nondiabetic control mice several miRNAs(miR192 miR-200bc miR21 and miR-1207-5p) are upreg-ulated in TGF-1205731-treated murine mesangial cells and inrenal glomeruli of mouse models of diabetes The TGF-1205731pathway is a master regulator of renal fibrosis which playsan important role in DN Among these miRNAs the best-studied one is miR-192 which has a conflicting expression inDNmiR-192 was reported to be upregulated in the glomeruliof streptozotocin- (STZ-) induced and dbdb diabetic mice[29]The upregulation of miR-192 expression is also shown intubular cells treatedwith TGF-1205731 [30]However other groupsfound a reduction in miR-192 in diabetic Apoeminusminus micewhich was associated with increased fibrosis [31 32] Investi-gation results explained that these complexities are due to celltype-specific effects of miRNA and differences in the animalmodels studied [33] while considering that decreasing ofmiR-192 is not pathogenic because Kato et al demonstratedthat miR-192 knockout (KO) mice had no kidney problemand milder kidney injury under diabetes Moreover somestudies had reported that the decreasing of miR-192 at laterstage can be just a result of nonspecific degradation of RNAsin progression of DN but not pathogenic [34 35] It hasreported that the level of miR-192 is increased in the earlystage of DN which can be prevented via suppressing thismicroRNA expression in the mice model of DN [36 37]Many articles describe the function of miR-192 in DN FirstmiR-192 can lead to upregulation of Col1a2 and Col4a1in mesangial cells They are key genes associated with thepathogenesis of DN [29] Second miR-192 can also regulateothermiRNAs such asmiR-216amiR-217 andmiR-200bc Itis known thatmiR-200 familymembers can regulate Zeb1 andZeb2MiR-200 can regulate collagen expression and promotethe autoregulation of TGF-1205731 in murine mesangial cells byinhibiting Zeb1 Moreover miR-216miR-217 also related toTGF-1205731-induced Akt activation and cellular hypertrophywhich are considered to be a pivotal feature ofDN [38]ThirdmiR-192 is reported to have an amplification loop with p53 inresponse to TGF-1205731 In this study the levels of TGF-1205731 p53and miR192 were all increased in the renal cortex of diabeticmice compared with control ones [34] Generally miR-192 isone of the major regulators in the pathologic mechanism ofDN

Similarly miR-21 is known to modulate the expressionand activities of important factors related to diabetic kidneydisease The mechanism of miR-21 regulating renal injuryis targeting Smad7 because downregulation of miR-21 canrestore Smad7 levels and suppressed activation of the TGF-120573 and NF-120581B signaling pathway [39] In the renal cortex of



5 lncRNA












8 Conclusions


Competing Interests


Acknowledgments


References









































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


















5 lncRNA












8 Conclusions


Competing Interests


Acknowledgments


References









































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



















8 Conclusions


Competing Interests


Acknowledgments


References









































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of





















of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















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ReviewArticle Epigenetic Regulations in Diabetic Nephropathydownloads.hindawi.com/journals/jdr/2017/7805058.pdf · 4 JournalofDiabetesResearch monitoring of diabetic patients. On