Tsis ntev los no kev nce qib hauv Epigenetics Ntawm Hnub Nyoog Txog Kab Mob Raum

Abstract:Lub raum kev laus tau nyiam ntau ntxiv hauv cov neeg laus niaj hnub no, vim tias cov neeg laus uas muaj hnub nyoog siab dhau los ua rau muaj kev cuam tshuam ntau dua.mob raumxws li mob raum raug mob(AKI) thiabmob raum mob(CKD). Tsis muaj qhov tseeb-txiav universal mechanism rau kev txheeb xyuasmuaj hnub nyoog txog kab mob raum, thiab yog li ntawd, lawv tsim ib qho kev kho mob loj heev thiabkev sib tw rau pej xeem kev noj qab haus huv. Epigenetics yog hais txog kev kawm txog kev hloov kho qub txeeg qub teg hauv kev tswj hwm ntawm noob caj noob ces tsis tas yuav muaj kev hloov pauv hauv cov kab ke DNA genomic. Ntau yam kev hloov pauv ntawm cov kab mob epigenetic xws li histone deacetylases (HDAC) inhibitors thiab DNA methyltransferase (DNMT) inhibitors tau raug npaj ua biomarkers muaj peev xwm thiab cov hom phiaj kho mob hauv ntau thaj chaw suav nrogkab mob plawv, kab mob ntawm lub cev, cov kab mob hauv paj hlwb, thiab neoplasms. Cov ntaub ntawv pov thawj nyob rau hauv xyoo tas los no qhia tau hais tias kev hloov kho epigenetic tau cuam tshuam rau hauvlub raum kev laus. Txawm li cas los xij, tsis muaj kev tshuaj xyuas yav dhau los tau ua kom muaj kev sib raug zoo ntawm kev sib raug zooepigenetics thiab muaj hnub nyoog txog kab mob raum. Nyob rau hauv qhov kev tshuaj xyuas no, peb lub hom phiaj los xaus qhov kev nce qib tsis ntev los no hauv cov txheej txheem epigenetic ntawm cov kab mob hauv lub raum muaj hnub nyoog, nrog rau kev sib tham txog kev siv cov tshuaj epigenetic modififiers raws li biomarkers muaj peev xwm thiab cov hom phiaj kho mob hauv thaj chaw.muaj hnub nyoog txog kab mob raum. Hauv cov ntsiab lus, cov txheej txheem tseem ceeb ntawm cov txheej txheem epigenetic suav nrog DNA methylation, hloov kho histone, thiab tsis-coding RNA (ncRNA) kev hloov pauv tau tag nrho cuam tshuam txog kev loj hlob ntawm cov kab mob hauv lub raum, thiab kev kho lub hom phiaj ntawm cov txheej txheem no yuav ua rau cov tswv yim kho tshiab. rau kev tiv thaiv thiab/los yog kev kho mob ntawm lub raum muaj hnub nyoog.

Ntsiab lus: epigenetics; kev hloov kho histone; DNA methylation; tsis-coding RNA kev cai;acov kab mob hauv lub raum

NYEM QHOV NO RAU CISTANCHE TO REATAGE-RELATED KIDNEY DISEASES

1. Taw qhia

Nrog rau txoj kev loj hlob sai ntawm kev lag luam kev lag luam thiab kev txhim kho kev noj qab haus huv, lub neej expectancy ntawm cov pej xeem sawv daws tau nce ntxiv, uas ua rau cov neeg laus cov neeg laus nce ntau heev [1]. Raws li World Health Organization (WHO) cov txheeb cais, nws kwv yees tias yuav muaj kwv yees li ob txhiab tus neeg muaj hnub nyoog tshaj 60 xyoo thoob ntiaj teb los ntawm 2050 [2–4]. Ntawm tag nrho cov teeb meem tshwm sim los ntawm kev laus, lub raum kev laus yog qhov tsis tseem ceeb. Txawm hais tias cov txheej txheem kev laus tsis ncaj qha ua rau mob raum, lub raum laus muaj qhov cuam tshuam rau ntau yam tsis zoo xws li ntshav siab, ntshav qab zib, rog, lossis thawj lub raum mob, uas tuaj yeem ua rau muaj kev txhim kho raum pathologies. Kev laus yog cuam tshuam nrog lub sijhawm tsis tuaj yeem nyob ntawm qhov poob ntawm lub raum ua haujlwm [5,6]. Cov yam ntxwv tseem ceeb ntawm lub raum muaj hnub nyoog suav nrog arteriosclerosis, glomerulosclerosis, tubular atrophy, thiab interstitial fibrosis [7]. Tshwj xeeb, ntau cov kev tshawb fawb tau qhia tias kev laus raug lees paub tias yog ib qho tseem ceeb ntawm kev ua rau muaj mob raum mob (AKI) thiab mob raum mob (CKD) hauv tag nrho cov pej xeem [7–9]. Tsis tas li ntawd, qhov tshwm sim ntawm cov neeg tuag vim lub raum tsis ua haujlwm yog nce thoob ntiaj teb sib npaug nrog cov neeg laus. Txawm li cas los xij, cov txheej txheem hauv qab ntawm lub raum laus tseem tsis tau qhia meej meej, thiab tseem yog qhov tseem ceeb ntawm kev tshawb fawb tam sim no. Yog li, kev txawj ntse daws cov teeb meem ntawm cov neeg laus laus yuav tsum txheeb xyuas cov hauv paus hauv paus ntawm qhov tshwm sim no nrog rau kev daws teeb meem zoo, uas yuav ua rau muaj txiaj ntsig zoo hauv zej zog.

Txog tam sim no, ntau lub tswv yim tau pom tias muaj kev cuam tshuam nrog lub hnub nyoog cuam tshuam nrog lub cev ua haujlwm poob qis xws li genome instability, telomere attrition, epigenetic alterations, poob ntawm proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, thiab stems. Kev hloov pauv ntawm kev sib txuas lus sib txuas lus [6,10], ntawm cov kev hloov pauv ntawm epigenetic yog cov cim tshiab ntawm kev laus hauv kaum xyoo dhau los [6,11]. Epigenetics feem ntau yog hais txog kev kawm txog cov txheej txheem molecular uas tswj cov noob qhia nrog rau phenotype yam tsis tau hloov pauv thawj DNA kab ke, uas feem ntau cuam tshuam nrog DNA methylation, histone post-translational modifications, chromatin remodeling, thiab kev tswj los ntawm non-coding RNAs (ncRNAs). Nyob rau hauv xyoo tas los no, lub luag haujlwm tseem ceeb ntawm kev hloov pauv ntawm epigenetic tau txais kev saib xyuas ntau ntxiv rau nws txoj kev koom tes hauv ntau yam kab mob thiab kev ua haujlwm ntawm lub cev. Tsis tas li ntawd, tam sim no tau lees paub tias DNA methylation thiab kev hloov pauv histone tau luam tawm thaum lub sij hawm embryonic txoj kev loj hlob thiab yuav tsum tau khaws cia rau hauv cov neeg laus kom noj qab haus huv thiab phenotypic stability [12]. Lub caij no, cov pov thawj loj hlob qhia tau hais tias kev laus ntawm cov cellular thiab cov kab mob hauv lub cev tau txuas nrog cov kev hloov pauv loj hauv cov kev hloov pauv ntawm epigenetic, ua rau hloov pauv cov qauv qhia cov qauv [13,14]. Tshwj xeeb, cov ntaub ntawv pov thawj tau pom tau tias muaj kev hloov pauv hauv kev hloov pauv xws li DNA methylation [15-18], kev hloov kho histone [19,20], thiab kev tswj hwm ntawm ncRNAs [21-23] tau koom nrog hauv kev pib thiab kev loj hlob ntawm lub raum kev laus [24] ]. Tsis ntev los no, kev hloov pauv hloov pauv hloov pauv hloov pauv, feem ntau suav nrog DNA methylation [11,17], hloov kho histone [20,25,26], thiab kev tswj hwm ntawm ncRNAs [27,28] kuj tau nce ntxiv hauv kev tsav tsheb muaj hnub nyoog ntsig txog lub raum. Txawm li cas los xij, tsis muaj kev tshuaj xyuas yav dhau los tau ua los ua kom muaj kev sib raug zoo ntawm epigenetics thiab cov kab mob hauv lub raum muaj hnub nyoog.

Epigenetics yog qhov kev tshawb fawb loj zuj zus thiab muaj kev txaus siab heev hauv kev siv cov kab mob epigenetics raws li kev kuaj mob biomarkers lossis cov hom phiaj kho mob ntawm cov kab mob laus [29]. Hauv qhov kev tshuaj xyuas no, peb sau cov kev nkag siab tam sim no ntawm lub luag haujlwm pathophysiological ntawm epigenetics, tshwj xeeb yog tsom rau DNA methylation, hloov kho histone, thiab ncRNAs hloov kho, hauv cov hnub nyoog ntsig txog raum kab mob. Nyob rau tib lub sijhawm, peb tsom mus rau kev cog lus siv cov kev hloov pauv ntawm cov kab mob epigenetic li cov cuab yeej muaj peev xwm rau kev kuaj mob thaum ntxov, kev kho mob, thiab kev tiv thaiv hnub nyoog ntsig txog kab mob raum. Ua ke, peb xav tias epigenetics plays lub luag haujlwm tseem ceeb hauv cov txheej txheem kev laus thiab tuaj yeem siv los ua cov hom phiaj kho mob rau kev kho mob raum muaj hnub nyoog, uas lav kev tshawb nrhiav ntxiv kom paub txog kev paub txog.

2. Phenotype thiab Mechanism ntawm Renal Aging

2.1. Molecular Mechanisms of Aging

Kev laus muaj feem cuam tshuam nrog lub sijhawm tsis tuaj yeem nyob ntawm qhov poob ntawm cellular, cov ntaub so ntswg, thiab lub cev ua haujlwm [30], uas tau nyiam cov neeg tshawb fawb thoob plaws hauv keeb kwm ntawm tib neeg [6]. Txawm hais tias txoj kev xav dawb radical ntawm kev laus tau npaj siab thaum ntxov li xyoo 1956 los ntawm Denham Harman [31], nws tsis yog txog xyoo 1983, thaum thawj cov kab mob nyob ntev tau raug cais tawm ntawm Caenorhabditis elegans, uas lub sijhawm tshiab hauv kev tshawb fawb laus pib [32 ]. Tam sim no, cov txheej txheem uas ua rau cov txheej txheem kev laus muaj xws li genomic instability, telomere attrition, epigenetic alterations, poob ntawm proteostasis, deregulated nutrient sensing, mitochondrial tsis ua hauj lwm, cellular senescence, thiab stem cell exhaustion raws li zoo raws li hloov intercellular kev sib txuas lus. Tsis tas li ntawd, cov txheej txheem kev laus kuj tseem cuam tshuam los ntawm lwm yam xwm txheej [33] xws li kev ua neej nyob tsis zoo thiab tsis zoo ib puag ncig, uas tseem cuam tshuam nrog kev laus ntawm lub cev [34,35]. Hauv qhov sib piv, kev noj qab haus huv ntawm kev noj qab haus huv xws li kev noj zaub mov zoo thiab kev tawm dag zog ib nrab tuaj yeem ua rau muaj kev laus thiab txhim kho lub neej zoo ntawm cov neeg laus [34,35]. Txawm hais tias muaj ntau qhov kev xav uas tau hais tawm hauv plaub lub xyoos dhau los los piav qhia qhov tshwm sim ntawm cov txheej txheem kev laus, cov txheej txheem tseeb uas tsav cov txheej txheem ntawm kev laus tseem tsis tau nkag siab tag nrho [36,37]

Txawm hais tias tib neeg txoj kev laus muaj feem cuam tshuam nrog kev poob qis hauv kev ua haujlwm ntawm ntau yam hauv nruab nrog cev, kev hloov pauv muaj nyob ntawm cov tib neeg uas muaj hnub nyoog tib yam vim muaj kev sib txuas ntawm caj ces thiab epigenetic yam tseem ceeb nrog rau ib puag ncig [24]. Yog li ntawd, tsis muaj tus qauv kub rau kev txiav txim siab seb yuav ua li cas rau kev laus noj qab haus huv, thiab tsis tuaj yeem ua ib qho biomarker muab qhov ntsuas tau thiab txhim khu kev ntseeg ntawm kev laus [38]. Tau ntau xyoo dhau los, cov neeg sib tw muaj peev xwm muaj peev xwm biomarkers ntawm kev laus tau raug npaj thiab tshuaj xyuas, tab sis tsis muaj leej twg tau hloov mus siv thoob ntiaj teb [39–41]. Kom meej meej, kev tshawb fawb tob ntxiv yog xav tau kom tau txais kev nkag siab zoo ntawm cov txheej txheem hauv qab ntawm cov txheej txheem kev laus los muab kev kwv yees tseeb ntawm kev laus thiab txheeb xyuas cov tib neeg uas muaj kev pheej hmoo siab ntawm kev tsim cov kab mob uas muaj hnub nyoog los yog kev tsis taus.

2.2. Pathological yam ntxwv ntawm lub raum laus

Kev laus muaj feem cuam tshuam nrog lub sijhawm tsis muaj kev cuam tshuam rau lub raum kev ua haujlwm thiab ua rau muaj kev cuam tshuam ntau ntxiv rau ntau yam mob raum lossis mob raum [5,6], ua rau muaj lub nra hnyav rau kev kho mob thoob ntiaj teb. Yuav kom nrhiav tau txoj hauv kev zoo los ncua kev laus lub raum, nws yog qhov tsim nyog los txheeb xyuas cov xwm txheej uas ua rau muaj hnub nyoog cuam tshuam txog kev hloov pauv hauv lub raum [3,42]. Kev noj qab haus huv ntawm lub raum nyob ntawm ntau yam xws li keeb kwm ntawm caj ces, poj niam txiv neej, haiv neeg, oxidative kev nyuaj siab, thiab mob o thiab cov kab mob epigenetic (xws li, DNA methylation, histone modifications), tag nrho cov no ua lub luag haujlwm tseem ceeb hauv lub raum kev laus [ 43] ib. Txawm hais tias cov ntaub ntawv tsim los ntawm ob qho tib si ntawm tes thiab tsiaj thwmsim qhia ntau txoj hauv kev uas muaj peev xwm tseem ceeb rau lub raum kev laus (Daim duab 1), cov ntaub ntawv txhawb nqa lawv txoj kev koom tes hauv tib neeg tam sim no tsis tshua muaj, nrog rau kev tshawb fawb ntxiv.

Daim duab 1. Schematic daim duab ntawm lub ntsiab mechanisms thiab phenotype ntawm lub raum aging. Nrog rau lub hnub nyoog zuj zus, muaj kev hloov pauv tseem ceeb hauv kev ua haujlwm thiab cov qauv ntawm lub raum. Ntau txoj hauv kev muaj hnub nyoog muaj feem cuam tshuam rau kev hloov pauv lub raum hauv cov neeg laus.

Nrog lub hnub nyoog nce, muaj kev hloov pauv tsis tau hauv lub raum ntawm ob qho tib si microscopic thiab macroscopic qib nrog rau kev kho mob thiab kev ua haujlwm. Nws tau raug tshaj tawm tias lub raum hnyav poob ntawm peb mus rau yim xyoo caum ntawm lub neej, nrog rau qhov kev poob qis tshaj plaws tshwm sim tom qab hnub nyoog 50 [44,45], tab sis kev tshuaj ntsuam xyuas qhia tau tias lub raum parenchymal ntim tseem tsis hloov [46]. Qhov no tej zaum yuav yog, nyob rau hauv loj, ntaus nqi rau them nyiaj hypertrophy ntawm unaffected nephrons nyob rau hauv teb rau poob ntawm nephrons induced los ntawm glomerulosclerosis thiab tubular atrophy [47]. Ib tug xov tooj ntawm cov qauv kev hloov pauv tshwm sim nyob rau hauv lub raum nrog kev laus, raws li pom nyob rau hauv daim duab 1, feem ntau suav nrog ib tug txo nephron tooj, txo tag nrho nephron loj, glomerular qab daus daim nyias nyias (GBM) thickness, glomerulosclerosis, interstitial fibrosis, arteriosclerosis, thiab tubular atrophy, uas. Thaum kawg ua rau txo qis raum ntshav ntshav (RPF) thiab glomerular filtration rate (GFR) [3,48]. Tsis tas li ntawd, lub raum laus pom muaj qhov ua rau muaj kev cuam tshuam ntau ntxiv xws li oxidative kev nyuaj siab, cov kab mob sib kis, thiab cov teeb meem fibrotic [49,50].

Ua ke, cov hnub nyoog ntsig txog cov qauv thiab kev hloov pauv hauv lub raum tuaj yeem ua rau lub raum tsis zoo rau ntau yam mob lossis mob raum.

2.3. Hnub nyoog txog raum tsis ua haujlwm

Txhawm rau kom nkag siab zoo dua ntawm cov txheej txheem kev laus, kom muaj txiaj ntsig zoo hauv nws, qhov sib txawv ntawm cov txheej txheem kev laus thiab hnub nyoog muaj feem cuam tshuam yog qhov tseem ceeb [51]. Cov ntsiab lus no muaj feem cuam tshuam rau ntau yam kab mob uas muaj hnub nyoog, tab sis tshwj xeeb tshaj yog muaj feem cuam tshuam hauv cov ntsiab lus ntawm kab mob raum. Txawm hais tias kev laus nws tus kheej tsis ua rau mob raum, lub hnub nyoog cuam tshuam txog cov qauv thiab kev ua haujlwm hloov pauv tuaj yeem ua rau cov neeg laus muaj ntau yam kab mob raum [7]. Piv txwv li, nyob rau hauv cov xwm txheej tsis zoo xws li ischemia-reperfusion raug mob (IRI) thiab nephrotoxicity insult co toxins, cov neeg laus tau nce siab rau AKI [42,52]. Ntau qhov kev tshawb fawb tau pom tias qhov tshwm sim ntawm CKD hauv cov neeg laus yog 3-13 npaug ntau dua li cov neeg hluas [53,54]. Tsis tas li ntawd, muaj pov thawj tias cellular senescence tau koom nrog hauv pathogenesis ntawm kab mob raum mob ntshav qab zib mellitus (DKD), thiab qhov hyperglycemia tseem ua rau cellular senescence hauv DKD [55,56]. Txawm hais tias lub raum cellular senescence yog qhov ua rau muaj hnub nyoog ntsig txog parenchymal glomerular lossis tubular cell shedding lossis poob, cellular senescence tsis tas yuav ua lub luag haujlwm tsis zoo rau txhua yam kab mob raum. Piv txwv li, autosomal dominant polycystic raum kab mob (ADPKD) yog vim tsis muaj kev tswj hwm ntawm lub raum tubular epithelial hlwb, thiab CDK inhibitor, roscovitine, tuaj yeem txo qhov kev loj hlob ntawm ADPKD feem ntau los ntawm kev txhawb nqa cellular senescence [57,58]. Tam sim no, txawm hais tias cov yam ntxwv hloov pauv ntawm lub raum laus tau piav qhia zoo, qhov sib txawv ntawm kev laus ib txwm muaj thiab cov kab mob hauv lub raum muaj hnub nyoog zoo dua ntxiv elucidation. Kev nkag siab txog etiologies ntawm lub raum kev laus thiab cov kab mob hauv lub raum muaj hnub nyoog tuaj yeem ua rau muaj txiaj ntsig zoo ntawm cov kev cuam tshuam ntawm cov tshuaj phylactic nrog rau cov tswv yim kho mob tshiab rau lub raum tsis ua haujlwm. Cov txiaj ntsig ntawm cov kev tshawb fawb tam sim no qhia tias kev hloov pauv ntawm epigenetic tshwm sim los ntawm ntau yam etiologies (xws li, uremia, cellular senescence, kev puas siab puas ntsws, kev ua neej, thiab ntau yam kab mob) tuaj yeem ua rau muaj kev loj hlob ntawm cov kab mob hauv lub raum (Daim duab 2) [24]. Lub caij no, nws tau lees paub ntau ntxiv tias kev hloov pauv ntawm epigenetic nyob rau hauv embryonic thiab cov neeg laus lub raum kev loj hlob yog kev sib txuas thiab dysregulation cuam tshuam rau hnub nyoog txog kab mob raum [12]. Yog li, kev nkag siab ntxiv txog kev hloov pauv ntawm epigenetic kev cai hauv embryonic thiab cov neeg laus lub raum kev loj hlob yuav txhim kho peb txoj kev nkag siab ntawm molecular mechanisms ntawm cov hnub nyoog ntsig txog kab mob raum thiab txhim kho cov kev kho tshiab tawm tsam cov kab mob no.

Ua ke, los ntawm cov kev tshawb fawb tam sim no, peb tuaj yeem txiav txim siab tias txawm tias muaj kev vam meej tau ua tiav hauv kev nkag siab ntawm lub raum kev laus thiab kev cuam tshuam ntawm lub raum kev ua haujlwm, cov kab mob ntawm cov kab mob hauv lub raum muaj hnub nyoog tseem tsis tau teb thiab lav kev tshawb nrhiav ntxiv.

Daim duab 2. Lub epigenetic toj roob hauv pes kho qhov kev sib tshuam ntawm etiologies thiab hnub nyoog txog lub raum tsis ua haujlwm. Ob leeg exogenous thiab endogenous etiologies tuaj yeem ua rau muaj kev hloov pauv hauv thaj chaw epigenetic uas cuam tshuam rau lub raum laus thiab lub cev.

3. Cov kab mob Epigenetics thiab hnub nyoog ntsig txog raum kab mob

Tam sim no, cov txheej txheem ua lub luag haujlwm rau lub hnub nyoog cuam tshuam txog kev ua haujlwm ntawm lub cev tsis tau nkag siab tag nrho, tab sis cov pov thawj loj hlob qhia tias kev hloov pauv ntawm epigenetic, feem ntau suav nrog DNA methylation aberrant, histone post-translational modifications, thiab kev tswj hwm los ntawm ncRNAs, ua lub luag haujlwm tseem ceeb hauv ntau yam. Cov neeg muaj hnub nyoog muaj feem cuam tshuam xws li neurodegenerative [59], kab mob plawv [60], thiab degenerative spinal stenosis [61] nrog rau ntau yam kab mob raum [24,62]. Hauv cov tshooj hauv qab no, peb yuav qhia txog cov kev paub tam sim no ntawm qhov cuam tshuam ntawm epigenetics hauv cov kab mob raum muaj hnub nyoog.

3.1. DNA Methylation nyob rau hauv cov hnub nyoog ntsig txog kab mob raum

Txawm hais tias covalent hloov kho ntawm DNA hauv paus tau piav qhia txij li xyoo 1948 los ntawm Hotchkiss [63], nws tsis yog txog 1969 uas Griffifith thiab Mahler tau hais tias cov kev hloov kho no yuav cuam tshuam txog kev hloov pauv ntawm cov noob qhia [64]. Tshwj xeeb, qhov kev hloov pauv loj hauv eukaryote DNA yog 5-methylcytosine (5mC) [65], uas feem ntau tshwm sim ntawm qhov thib tsib ntawm lub nplhaib pyrimidine ntawm cytosine. DNA methylation, thawj qhov kev txheeb xyuas epigenetic mechanism, uas tshwm sim feem ntau ntawm cytosine-phosphate-guanine (CpG) dinucleotides nyob rau hauv cov gene txhawb cov cheeb tsam [66], yog koom tes hauv kev tswj cov noob qhia los ntawm inhibiting tshwj xeeb transcription yam khi rau DNA los yog recruiting mediators ntawm chromatin. hloov kho (piv txwv li, histone-modifying enzymes) [67–70]. Hauv cov tsiaj nyeg, DNA methylation qauv yog niaj hnub tsim thiab tswj los ntawm peb DNA methyltransferases (DNMT) [70,71] suav nrog DNMT1, DNMT3a, thiab DNMT3b, thaum qhov sib txawv, DNA demethylation tuaj yeem ua tiav los ntawm kaum-kaum translocation (TET) enzymes. los ntawm kev hloov 5mC rau 5-hydroxymethylcytosine (5hmC) [72,73].

Txoj cai tswj hwm ntawm DNA methylation thiab demethylation yog ib qho tseem ceeb tshaj plaws ntawm kev tswj hwm cov txheej txheem epigenetic hauv eukaryotic hlwb, uas txog rau tam sim no, tsis tau nkag siab tag nrho. Cov pov thawj ntxiv tau pom tias qhov tsis zoo DNA methylation ntawm cov chaw tshwj xeeb CpG tuaj yeem ua cov biomarkers rhiab heev los txheeb xyuas cov tib neeg muaj kev pheej hmoo rau cov kab mob muaj hnub nyoog [61,74]. Tshwj xeeb, cov kab mob raum muaj hnub nyoog xws li CKD thiab ESRD yog ib qho teeb meem kev noj qab haus huv rau pej xeem thoob ntiaj teb vim nws muaj kev mob siab rau cov neeg laus. Ntau qhov kev tshawb fawb tau tshawb pom zoo txog kev sib koom ua ke ntawm DNA methylation qauv thiab hnub nyoog txog kab mob raum [75–77]. Piv txwv li, ib txoj kev tshawb fawb tsis ntev los no tau tshawb xyuas qhov kev hloov pauv ntawm genome-wide hauv DNA methylation hauv lub raum biopsy kuaj tau los ntawm 95 tus neeg mob lub raum noj qab haus huv hnub nyoog ntawm 16 txog 73 xyoo [11]. Tag nrho ntawm 92,778 CpG methylation qhov chaw tau txheeb pom tias muaj feem cuam tshuam nrog lub hnub nyoog pub dawb los ntawm kev tshuaj xyuas ntawm genome-wide hloov hauv DNA methylation (ntau dua 800,{16}} CpG qhov chaw) (FDR<0.05), corresponding to 10,285 differentially methylated regions. Interestingly, these regions were most frequently located in the Wnt/β-catenin signaling pathway-related genes including the dickkopf Wnt signaling inhibitors (DKK), several SOX transcription factors, Wnt inhibitory factor 1 (WIF1), secreted frizzled-related protein 2 (SFRP2), retinoic acid receptor alfa and beta (RARA and RARB), and so on. Hypermethylation in the promoter region of these Wnt signaling inhibitor genes may contribute to the activation of Wnt/β-catenin signaling in the aged kidney. Furthermore, Wnt/β-catenin signaling, a conserved signaling pathway in organ development, is kept silent in normal adult kidneys [78,79], which is reactivated predominately in tubular epithelial cells in a variety of CKD models [80]. Thus, hypermethylation of these Wnt signaling inhibitor genes induces activation of Wnt/β-catenin signaling, which may lead to aging-related renal changes by triggering tubular epithelial cell transition to mesenchymal or senescent phenotype and promoting renal fibrosis. This study clearly revealed a causal relationship between DNA hypermethylation and age-associated renal dysfunction [11], indicating that DNA methylation alterations could be a new class of potential non-invasive diagnostic and prognostic biomarkers for age-related kidney diseases. Moreover, numerous clinical observations and animal studies have demonstrated that DNA methylome alterations are implicit in the development and progression of CKD [81–84]. For example, an epigenome-wide association study (EWAS) was performed to investigate the genome-wide methylation profiles in whole blood samples from 4859 aging adults, which demonstrated that the epigenetic signatures were significantly associated with kidney function and CKD as well as with the clinical endpoint renal fibrosis [84]. In this study, the researchers identified 19 CpG sites associated with eGFR and CKD from whole blood samples, among which five CpG sites were associated with renal fibrosis and showed consistent and significant DNA methylation changes in renal cortical biopsy samples from CKD patients. The study revealed that eGFR-associated CpG sites were significantly enriched in regions bound to serval transcription factors including Early B-cell Factor1 (EBF1), E1A Binding Protein P300 (EP300), and CCAAT/enhancer-binding protein beta (CEBPB), highlighting the impact of epigenetic modifications on renal function. Moreover, previous studies have demonstrated that several targeted genes regulated by CEBPB, EBF1, and EP300 are essential for kidney development and function [85–88], suggesting that methylation alterations of CEBPB, EBF1, and EP300 target genes may block the regulation of CEBPB, EBF1, and EP300 on their target genes, leading to the development of CKD. Thus, CEBPB, EBF1, and EP300 may serve as promising candidates for future experimental studies to illuminate the underlying gene regulatory mechanisms linking differential DNA methylation to kidney function in health and disease. 

Txawm hais tias muaj ntau qhov kev tshawb fawb txog genome-wide koom haum thiab kev tshawb fawb ntawm epigenome-wide koom haum tau txheeb xyuas qhov kev hloov pauv tseem ceeb hauv DNA methylation nrog rau kev laus thiab cov kab mob raum uas muaj hnub nyoog, tam sim no tseem tsis muaj cov pov thawj ncaj qha qhia tias kev hloov pauv hauv cov qauv kev qhia cov noob thiab cov noob. - tshwj xeeb DNA methylation cuam tshuam rau lub raum laus [17,18]. Ib txoj kev tshawb fawb tsis ntev los no tau muab pov thawj muaj zog rau kev nthuav tawm cov yam ntxwv tseem ceeb ntawm lub raum laus [17]. Tsis ntev los no, Gao thiab cov npoj yaig tau tshaj tawm tias kev txhaj tshuaj ntev ntev ntawm D-galactose (D-gal)-vim kev laus lossis lub raum kev laus ua rau lub raum tseem ceeb ua rau muaj kev cuam tshuam tseem ceeb ntawm KLOTHO thiab antiaging factor nuclear erythroid-derived 2-zoo li 2 (NRF2) qhia. , nrog rau kev nthuav qhia ntau ntxiv ntawm DNMTs (subtypes ntawm DNMT1, DNMT3a, thiab DNMT3b) nrog rau hypermethylation ntawm NRF2 thiab KLOTHO gene txhawb nqa [17]. Kev tswj hwm ntawm DNA-demethylating tus neeg saib xyuas, SGI-1027 thiab OLP, txo cov DNA methylation ntawm NRF2 thiab KLOTHO tus txhawb nqa thiab txo cov D-gal-induced aging-txog cov qauv thiab kev ua haujlwm hloov pauv hauv nas raum. Qhov tshwj xeeb tshaj yog, qhov cuam tshuam rau lub raum kev laus ntawm SGI-1027 hauv D-gal-induced aging nas tau raug tshem tawm los ntawm kev ntsiag to KLOTHO hauv vivo. Los ntawm txoj kev tshawb no, peb tuaj yeem txiav txim siab tias dysregulation ntawm DNMT1 / 3a / 3b tseem ceeb ua rau lub raum laus txheej txheem thiab kev cuam tshuam ntawm epigenetic nrog DNA-demethylating cov neeg ua haujlwm tuaj yeem txo cov kev laus ntawm lub raum, qhia tias kev hloov pauv ntawm cov qauv qhia tshwj xeeb thiab genomic DNA methylation tuaj yeem muaj tseeb. cuam ​​tshuam rau lub raum kev laus. Yog li, txhim kho cov tswv yim kho mob txhawm rau thim rov qab cov hnub nyoog cuam tshuam nrog kev hloov pauv tsis zoo ntawm epigenetic yuav ua rau muaj kev txhim kho ntawm cov kev kho tshiab tshiab uas tuaj yeem ncua lossis txo lub raum laus thiab muaj hnub nyoog cuam tshuam rau lub raum.

Los ntawm kev tshawb fawb tam sim no ntawm DNA methylation hauv cov kab mob hauv lub raum muaj hnub nyoog (Table 1), peb tuaj yeem txiav txim siab tias DNA methylation tuaj yeem ua rau muaj kev tswj hwm tseem ceeb hauv ob qho tib si lub raum laus thiab cov hnub nyoog ntsig txog raum kab mob. Txawm li cas los xij, cov kev tshawb fawb tam sim no nyob deb ntawm qhov txaus los qhia txog cov txheej txheem molecular hauv qab DNA methylation hloov pauv hauv cov hnub nyoog ntsig txog raum kab mob. Tsis tas li ntawd, feem ntau ntawm cov kev tshawb fawb no tsis muaj vivo sim validation. Yog li ntawd, kev tshawb fawb ntau ntxiv tsom rau DNA methylation hloov pauv hauv cov hnub nyoog ntsig txog kab mob raum thiab kev siv tshuaj kho mob yav tom ntej.

Table 1. DNA methylation hauvmuaj hnub nyoog txog kab mob raum.