Kev sib cuam tshuam ntawm Ntev Tsis-Coding RNAs Thiab MicroRNAs cuam tshuam tus kab mob Phenotype hauv ntshav qab zib thiab mob ntshav qab zib raum kab mob
Mar 12, 2022
Abstract:Loj-scale RNA sequencing thiab genome-wide profileing cov ntaub ntawv qhia qhov kev txheeb xyuas ntawm ib pawg heterogeneous ntawm noncoding RNAs, hu ua ntev noncoding RNAs (lncRNAs). Cov lincRNAs no ua lub luag haujlwm tseem ceeb hauv kev noj qab haus huv thiab kab mob txheej txheem hauv ntshav qab zib thiab mob qog noj ntshav. Lub koom haum tseem ceeb ntawm kev qhia tsis meej ntawm lncRNAs hauv ntshav qab zib thiab ntshav qab zibmob raumtau qhia. LncRNAs tswj ntau lub hom phiaj thiab tuaj yeem ua haujlwm raws li daim txhuam cev rau kev tswj hwm microRNAs, uas cuam tshuam cov kab mob phenotype hauvlub raum.Qhov tseem ceeb, lncRNAs thiab microRNAs tuaj yeem tswj hwm cov txheej txheem bidirectional lossis crosstalk, uas yuav tsum tau tshawb xyuas ntxiv. Cov kev tshawb fawb no muab qhov muaj peev xwm tshiab uas lncRNAs tuaj yeem siv los ua cov hom phiaj kho mob rau ntshav qab zib thiab ntshav qab zib.kab mob raum. Ntawm no, peb tham txog cov haujlwm thiab cov txheej txheem ntawm kev ua ntawm lncRNAs, thiab lawv cov kev sib tham sib tham nrog microRNAs, uas muab kev pom thiab cog lus raws li cov hom phiaj kho mob, hais txog lawv lub luag haujlwm hauv cov kab mob ntshav qab zib thiab ntshav qab zib.mob raum.
Ntsiab lus:ntev noncoding RNAs; microRNAs hauv lub raum; raum fibrosis; EMT; EndMT; ntshav qab zib mellitus; mob ntshav qab zib raum; lub raum
CISTANCHE yuav txhim kho rau lub raum/ raum mob
Ntev Tsis-Coding RNA (lncRNA)Ntev tsis-coding RNAs (LncRNAs) account rau cov chav kawm loj ntawm noncoding RNAs nyob rau hauv genome thiab yog cov kab ntawv sau ntev dua 200 nucleotide sequences uas muaj cov yam ntxwv zoo sib xws.nrog mRNAs [1]. Feem ntau LncRNAs tau sau los ntawm RNA polymerase II thiab tau capped ntawm 50 kawg thiab splicing thiab polyadenylated tail ntawm 30 kawg. LncRNAs tau txhais cov cheeb tsam txhawb nqa [1]. Txawm li cas los xij, piv rau mRNA, lncRNAs tsis muaj qhib cov ntawv nyeem (ORFs) thiab muaj tsawg dua exons (lncRNAs muaj nyob ib ncig ntawm 2.8 exons whereas mRNA muaj 11 exons). LncRNAs tuaj yeem muab sau ua tag nrho lossis ib nrab ntawm cov ntawv sau tseg ntawm cov tshuaj tiv thaiv ntuj (NAT) rau cov noob caj noob ces, lossis nyob nruab nrab ntawm cov noob lossis hauv introns [1]. Qee cov lncRNAs los ntawm pseudogenes [2]. LncRNAs tuaj yeem muab faib ua ntau hom subtypes raws li lawv txoj haujlwm (xws li antisense, intergenic, overlapping, intronic, bidirectional thiab recessed) thiab transcriptional kev taw qhia nyob rau hauv relation mus rau lwm yam noob [3,4].
Synthesis txheej txheem thiab qhov chawGene qhia profiling thiab nyob rau hauv situ hybridization kev tshawb fawb tau pom tias qhov kev qhia ntawm lncRNAs tuaj yeem yog cov ntaub so ntswg- thiab cov xovtooj ntawm tes, thiab tej zaum yuav txawv txav, ib ntus lossis teb rau stimuli [5]. Ntau lncRNAs nyob rau hauv lub nucleus, txawm li cas los xij, qee qhov yog cytoplasmic lossis nyob hauv ob lub nucleus thiab cytoplasm. LncRNAs yog cov tswj hwm tseem ceeb ntawm cov noob qhia thiab muaj kev ua haujlwm hauv ntau cov txheej txheem ntawm tes thiab kev loj hlob [5]. LncRNAs ua haujlwm los ntawm ob qho tib si inhibition thiab ua kom cov noob [6]. LncRNAs tau muab faib ua plaub pawg raws li lawv qhov chaw nyob hauv genome: (1) cov intergenic lncRNAs, (2) qhov kev nkag siab lossis antisense lncRNAs, (3) intronic lncRNAs thiab (4) cov ntawv sau ua tiav; cov lncRNAs nyob hauv ib lub noob-loci uas tsis muaj ORF [6,7]. Raws li lawv cov dej num, lncRNAs tau ua lub teeb liab, decoy, scaffold, qhia, enhancer RNAs thiab luv peptides [8,9]. Lub teeb liab lncRNA ua raws li lub teeb liab molecular uas tswj cov txheej txheem hloov pauv [10]. Decoy lncRNAs ua los ntawm kev txo qhov muaj cov molecules tseem ceeb uas koom nrog hauv kev tswj hwm noob. Cov lncRNAs hloov cov qib transcription los ntawm sequestering regulatory yam, thiab microRNAs, li no txo lawv cov theem qhia [11]. Cov chav kawm scaffold ntawm lncRNAs muab cov qauv kev txhawb nqa rau cov proteins nyuaj [12] thiab kev hloov pauv kev ua haujlwm lossis kev tsim txom tau raug txiav txim siab nyob ntawm seb hom kev tswj hwm cov proteins thiab RNAs uas muaj [13]. Qhia lncRNAs cuam tshuam nrog ribonucleoproteins complex thiab cuam tshuam rau qib transcriptional qib [14].
LNCs nyob rau hauv Diabetic raum Kab MobMuaj pov thawj tau qhia txog lub luag haujlwm tseem ceeb ntawm lncRNAs hauv pathophysiology ntawm ntshav qab zibmob raum(DKD), thiab crosstalk ntawm lncRNAs thiab DKD tau tshaj tawm nyob rau xyoo tsis ntev los no [15–19]. Hloov pauv qib ntawm lncRNAs ua lub luag haujlwm tseem ceeb hauv kev txhim kho cov proteinuria thiab txuam nrog ntshav qab zib nephropathy (DN) [15,20]. LncRNAs koom nrog hauv kev nce qib ntawmmob raumlos ntawm kev tswj hwm ntawm ntau yam tseem ceeb, xws li cov txheej txheem pathologic hauv mesangial hlwb, podocytes, reactive oxidative hom, epithelial-to-mesenchymal hloov (EMT), endothelial-to-mesenchymal hloov (EndMT) thiab kev ua ntawm microRNAs [21-23] .
Ob peb lncRNAs koom nrog cov kev cai ntawmmob raum(Table 1). Piv txwv li, plasmacytoma variant translocation (PVT1) koom nrog kev txhim kho DN los ntawm kev tswj hwm ECM tsub zuj zuj. PVTI yog thawj qhov tsis-coding RNA tau tshaj tawm tias muaj feem cuam tshuam nrogmob raum, uas yog heev qhia nyob rau hauv tib neeglub raummesangial hlwb nyob rau hauv cov ntshav qabzib siab thiab txhawb kev qhia ntawm fibronectin protein, hom IV collagen, TGF- 1 thiab hom I plasminogen activator inhibitor [20,24,25]. Metastasis-associated ntsws adenocarcinoma transcript 1 (MALAT1) yog aberrantly upregulated nyob rau hauv thaum ntxov DN [26–28]. MALAT1 pib mob thiab oxidative kev nyuaj siab; cov kab mob pathogenic no tswj cov piam thaj-stimulated induction ntawm proinflammatory cytokines IL-6 thiab TNF- los ntawm activating serum amyloid antigen 3. Cov kev hloov no hloov endothelial cell stability hauv DN [20,29]. Gm4419 yog nyob rau hauv chromosome 12 thiab yog tus tswj hwm ntawm cov khoom siv hluav taws xob nuclear-kappa lub teeb-chain enhancer ntawm activated B hlwb (NF-κB), uas yog ib qho tseem ceeb inflammatory yam rau DN [20,30]. Gm4419 cuam tshuam nrog p50 thiab induces NF-κB / NLRP3 inflammasome teeb liab transduction txoj kev nyob rau hauv mesangial hlwb, uas yog txuam nrog o, fibrosis thiab proliferation nyob rau hauv high-glucose tej yam kev mob [30]. NR_033515 tau raug kho kom zoo hauv cov ntshav ntawm cov neeg mob DN [31]. Overexpression ntawm NR_033515 txhawb nqa mesangial cell proliferation thiab inhibits apoptosis [31]. NR_033515 tau pom tias yuav txhim kho cov kev qhia gene theem ntawm cov noob muaj feem cuam tshuam txog kev loj hlob, fibrosis-sociated genes thiab EMT cov cim los ntawm kev tsom miR-743b-5p [31].Lub raum-kev tshem tawm tshwj xeeb ntawm Erbb4-IR tau pom tias muaj kev tiv thaiv los tiv thaiv DN teeb meem [32]. Erbb4-IR inhibits theem qhia ntawm reno-tiv thaiv miR-29b. Yog li ntawd, theem ntawm fibrosis tau txhim kho los ntawm Erbb4-IR thiab ntshav qab ziblub raum[32]. Antisense mitochondrial noncoding RNA-2 (ASncmtRNA-2) yog mitochondrial lncRNA [33]. ASncmtRNA-2 yog upregulated nyob rau hauv aging thiab senescence nyob rau hauv endothelial hlwb [33]. ASncmtRNA-2 induces oxidative kev nyuaj siab thiab ua rau tubular raug mob los ntawm (i) ceev lipid peroxidation thiab protein crosslinking, (ii) kev puas tsuaj rau DNA, thiab (iii) txhawb inflammatory pathways, xws li NF-κB thiab transforming kev loj hlob factor{{ 8}} (TGF 1) [33]. Lnc-MGC yog tswj hwm los ntawm ER kev ntxhov siab cuam tshuam txog kev hloov pauv, CHOP (C/EBP homologous protein), thiab los ntawm TGF 1-dependent thiab ywj siab mechanisms [34]. ER kev ntxhov siab nce rau hauv cov neeg mob uas muaj kev vam meej DN [34]. Nuclear enriched transcript-1 (NEAT1) tau qhia ntau heev hauv cov ntshav qabzib siab thiab cuam tshuam nrog AKT / mTOR txoj hauv kev [35,36]. NEAT1 inhibition ua rau txo qis hauv qib TGF 1, FN thiab COL4A1 hauv DN [36]. NEAT1 txhawb nqa cov ntshav qabzib siab mesangial cell hypertrophy los ntawm kev tsom mus rau miR- 222-3p/CDKN1B axis [37]. Ib yam li ntawd, lncRNA ERBB4-IR tau koom nrog hauv kev txhim kho lub raum fibrosis hauv ntshav qab zib thiab nws qhov kev ntsiag to hauv cov nas mob ntshav qab zib tiv thaiv albuminuria thiab cov txheej txheem fibrogenic [32,38].
CISTANCHE yuav txhim kho lub raum / raum mob ntshav qab zib
Conversely, qhov kev qhia ntawm CYP4B1-PS1-001, uas upregulates cov nucleolin protein theem, yog suppressed nyob rau hauv high-glucose tej yam kev mob [39,40]. CYP4B1-PS1-001 overexpression suppresses qib ntawm FN, COL4A1 thiab proliferation markers nyob rau hauv cov nas mob ntshav qab zib [40]. Lwm qhov piv txwv ntawm reno-tiv thaiv lncRNA yog lncRNA ENSMUST00000147869, uas lub hom phiaj ECM ntau lawm hauvlub raumntawm cov nas mob ntshav qab zib [41]. ENSMUST00000147869 cuam tshuam ECM synthesis thiab ua rau txo qis ntawm fibronectin thiab collagen IV hauv mesangial hlwb nyob rau hauv cov ntshav qabzib siab [41], txawm tias lub luag haujlwm tseeb ntawm lncRNA no tsis paub. TUG1 ua haujlwm raws li kev tawm tsam ntawm miR-377. miR-377 ncaj qha tsom rau 30UTR ntawm PGC-1 thiab cov cim fibrosis. Yog li ntawd, TUG1 upregulates qib ntawm PGC{10}} thiab alleviates ECM ntau lawm thiab downregulates cov theem ntawm proinflammatory cytokines nyob rau hauv high-glucose stimulated mesangial hlwb [42]. Myocardial infarction-associated transcript (MIAT), tseem hu ua retinal noncoding RNA 2 (RNCR2), tau paub tias koom nrog myocardial infarction [35]. MIAT tswj hwm cell viability los ntawm stabilizing nuclear factor erythroid 2-related factor 2 (NRF2) qhia hauvlub raumtubules [20]. NRF2 pathologically thiab functionally tiv thaiv covlub raumtiv thaiv kab mob ntshav qab zib [43]. Interestingly, qhov kev qhia ntawm Nrf2 tuaj yeem txhim kho los ntawm MIAT overexpression hauv qabzib-kho.renal tubular epithelial cell kab [44]. Cancer susceptibility neeg sib tw 2 (CASC2) muaj cov haujlwm tseem ceeb hauv cov qog nqaij hlav [45]. Downregulated qhia ntawm CASC2 tau pom nyob rau hauv cov ntshav thiabraumcov ntaub so ntswg hauv cov ntshav qab ziblub raumthiab yog kwv yees txog kev mob ntshav qab zib [46]. Cov qib plasma qis ntawm CASC2 yog txuam nrog kev pheej hmoo siab duaraum tsis ua haujlwmhauv cov neeg mob DN [47,48]. Lwm lncRNA, 1700020I14Rik, uas nyob rau hauv chromosome 2 (Chr2: 119594296–119600744), ua haujlwm raws li endogenous RNA thiab tswj cov theem qhia ntawm microRNAs hauv ntshav qab zib [20,49]. Overexpression ntawm 1700020I14Rik suppresses qhia theem ntawm miR-34a-5p los ntawm Sirt1/HIF-1 teeb liab txoj kev thiab accelerates fibrosis hauv mesangial hlwb [49]. CYP4B1-PS1-001 yog downregulated nyob rau hauv thaum ntxov DN [40]. Nws overexpression inhibits fibrosis ntawm mesangial hlwb los ntawm kev cuam tshuam nrog nucleolin [40]. Gm15645 yog downregulated hauv DN thiab siab-glucose-stimulated, kab lis kev cai podocytes [50]. Lub tshuab ntawm Gm15645 yog qhov tsis sib xws ntawm Gm5524, uas cuam tshuam rau podocyte cell tuag thiab kev tswj hwm autophagy hauv DN [50]. LINC01619 tswj miR-27a/FoxO1 (forkhead box protein O1) thiab ER stress-associated podocyte cell raug mob hauv ntshav qab zib [51]. Downregulated qhia theem ntawm LINC01619 yog txuam nrog proteinuria thiab poob rau hauvlub raum ua haujlwmhauv cov neeg mob DN; yog li ntawd, lub hom phiaj LINC01619 yog ib qho ntawm cov kev xaiv kho mob uas muaj peev xwm rau kev kho mob ntawm DN [51]. Daim duab 1 qhia txog lncRNA kev koom tes hauv kev cuam tshuam EMT, EndMT thiab glomerular raug mob hauv ntshav qab zib nephropathy.
LncRNAs Kev Koom Tes Hauv Txoj Cai ntawm EMTEMT koom nrog ntau cov txheej txheem uas cov hlwb epithelial poob lawv cov yam ntxwv epithelial thiab tau txais cov khoom ntawm cov hlwb mesenchymal [52–57]. Daim duab 1 qhia txog kev koom tes ntawm lncRNAs hauv kev tswj hwm ntawm EMT, EndMT thiab mesenchymal hlwb. Cov hlwb epithelial feem ntau cuam tshuam nrog lawv cov hlwb nyob ze. Nyob rau hauv sib piv, mesenchymal hlwb tsis tsim intercellular adhesion complexes [58]. Mesenchymal hlwb yog elongated nyob rau hauv cov duab thiab pom qhov kawg-rau-kawg polarity thiab focal adhesions, tso cai rau kom muaj peev xwm tsiv teb tsaws [58]. Lub luag haujlwm tseem ceeb ntawm fibroblasts, uas yog prototypical mesenchymal hlwb uas pom nyob rau hauv ob peb cov ntaub so ntswg, yog kom muaj kev ncaj ncees ntawm lub cev los ntawm secreting extracellular matrix (ECM). Fibroblast-specific protein 1 (FSP-1), alpha-smooth leeg actin (SMA), vimentin, fibronectin thiab collagen kuv yog cov cim uas qhia cov khoom mesenchymal hauv cov ntshav qab zib.lub raum[58–60]. Kev mob tshwm sim hauv kev nrhiav neeg ua haujlwm ntawm ntau hom hlwb uas koom nrog hauv induction ntawm EMT cov txheej txheem. Kev nce qib ntawm TGF 1, platelet-derived growth factor (PDGF), epidermal growth factor (EGF) thiab fibroblast growth factor-2 (FGF-2) pab txhawb rau cov txheej txheem EMT [59–61]. MALAT1, NR_033515, Erbb4-IR, GAS5 thiab CJ241444 koom nrog kev raug mob ntawm tubular thiab pab txhawb rau cov txheej txheem EMT thaum MIAT thiab LncRIAN tau qhia txog kev tiv thaiv tubular thiab tej zaum yuav tau tswj hwm cov txheej txheem EMT hauv cov ntshav qab zib.lub raum(Daim duab 1).
LncRNAs Kev Koom Tes Hauv Txoj Cai ntawm EndMTEndothelial hlwb tsim fibroblasts los ntawm kev hloov pauv, hu ua EndMT [57, 58,62–65]. EndMT yog tus cwj pwm los ntawm kev poob ntawm endothelial cell phenotypes thiab nce ntawm mesenchymal proteins [58,62,64–67]. thiab koom nrog cov txheej txheem fibrogenic hauvlub raumthiab, hauv ntshav qab ziblub raum,tuaj yeem hloov kho lub cev thiab kev ua haujlwm ntawm lwm cov hlwb nyob sib ze [58,62,65,68]. Pathological stimuli xws li mob, ntshav qab zib thiab kev laus cuam tshuam EndMT cov xwm txheej hauv lublub raum[69]. Endothelial SIRT3, lub nuclear receptor glucocorticoid receptor (GR) thiab xovtooj ntawm tes FGFR1 yog qhov tseem ceeb regulators ntawm TGF signaling thiab EndMT hauv ntshav qab zib.lub raum[70–73]. Covraums ntawm cov nas mob ntshav qab zib tau pom ob qho kev mob glomerular sclerosis thiab tubulointerstitial fibrosis, uas tau cuam tshuam nrog kwv yees li 40 feem pua ntawm tag nrho FSP-1- cov hlwb zoo thiab 50 feem pua ntawm SMA-positive stromal hlwb yog CD31- zoo [74] . Ib yam li ntawd, hauv lublub raumntawm COL4A3 knockout nas, 45 feem pua ntawm tag nrho SMA-zoo fibroblasts thiab 60 feem pua ntawm tag nrho FSP-1-zoo fibroblasts yog CD31-zoo, qhia tias cov fibroblasts no yog cov keeb kwm ntawm endothelial thiab EndMT yuav ua rau muaj kev cuam tshuam rau Kev loj hlob thiab kev loj hlob ntawm lub raum fibrosis [74] Thaum lub sij hawm txheej txheem ntawm EndMT, biochemical kev hloov pauv ua rau txo qis ntawm cov cim endothelial thiab qhov nce ntawm cov cim mesenchymal xws li FSP-1, SMA, cov leeg nqaij du 22-alpha (SM22), N-cadherin, fibronectin. , vimentin, hom I thiab III collagen, nestin, pawg sib txawv, 73 (CD73), matrix metalloproteinase-2 (MMP-2) thiab matrix metalloproteinase-9 (MMP- 9) ) [58,75,76] ib. MALAT1, Erbb4-IR thiab ASncmtRNA2 ua rau endothelial cell raug mob thiab tej zaum yuav cuam tshuam nrog EndMT-txuas rau lub raum fibrosis (Daim duab 1). LncRNA H19 yog txuam nrograumfibrosis los ntawm kev ua kom cov txheej txheem EndMT hauv ntshav qab zib (Daim duab 1).
CISTANCHE yuav txhim kho lub raum / raum kab mob
LNCs Interaction nrog microRNA Lub miRNA thiab lncRNA kev sib cuam tshuam yog ib qho ntawm cov txheej txheem rau kev tswj hwm cov noob qhia [77]. Qhov kev tswj hwm ntau theem no koom nrog yuav luag tag nrho cov txheej txheem physiological thiab cellular ntawm qib transcriptional, post-transcriptional thiab post-translational theem [77,78]. Hauv qee qhov kev tshawb fawb, nws tau tshaj tawm tias miRNA ua rau lncRNA lwj [77]. Ntawm qhov tsis sib xws, lncRNAs tsim miRNAs, ua raws li miRNA sponges thiab miRNA decoys, thiab sib tw nrog miRNA rau kev khi ntawm mRNAs [77]. LncRNA genes tuaj yeem khaws cov microRNAs thiab cov microRNAs tuaj yeem tso tawm los ntawm kev ua haujlwm tom qab. Piv txwv li, lncRNA PVT1 ua haujlwm ua tus tswv ntawm miR-1207-5p thiab tau cuam tshuam hauv DN [79]. microRNAs feem ntau tshwm sim hauv pawg, tau nyob hauv thaj chaw rau PVT1 qhov chaw, thiab tau tswj hwm los ntawm cov piam thaj ntau thiab cuam tshuam rau cov khoom sib txuas ntawm cov cellular matrix [80]. miRNA pawg nyob rau hauv lncRNAs tuaj yeem loj heev raws li pom los ntawm ib pawg mega ntawm ntau tshaj 40 miRNAs harbored hauv lnc-MGC [34]. Cov pawg no yog induced nyob rau hauv cov ntshav qab zib glomeruli los ntawm endoplasmic reticulum kev ntxhov siab signaling, uas teb rau siab qabzib thiab TGF -activation ib yam nkaus [34].
Kev sib cuam tshuam ntawm microRNAs thiab lncRNAs yog qhov tseem ceeb los kawm txog cov kauj ruam tseem ceeb hauv kev nce qib DN. DN nas qhia kev sib cuam tshuam ntawm lncRNA CJ241444-miR-192 uas induces TGF 1/Smad3 signaling [81] thiab lncRNA Erbb4- IR-miR-129b activates collagen noob thiab ECM gene thiab li no,mob raum[82]. Cov lncRNAs tuaj yeem ua raws li miRNA sponges [32,81]. Ib yam li ntawd, lncRNA PVT-1 koom nrog hauv ECM tsub zuj zuj ntawm kev ua ntawm nws cov miRNAs, miR-1207-5p thiab miR-1207-3p [25]. Nyob rau hauv cov ntshav qabzib siab, kev qhia ntau dua ntawm PVT-1 thiab nws cov miRNAs ua rau muaj kev nce ntxiv ntawm TGF 1/Smad3 signaling thiab ECM tsub zuj zuj [25]. Ib yam li ntawd, miR-379 pawg uas tswj hwm los ntawm ER kev ntxhov siab hauv DN thiab lncMGC kuj tau tuav hauv tib pawg [34]. LncMGC tswj cov kev qhia ntawm miR-379 pawg, thiab kev txhim kho ntawm miR-379 pawg induces ECM tsub zuj zuj thiab lub raum hypertrophy [34]. Yog li, antagonism ntawm lncMGC kev qhia tuaj yeem siv los ua qhov kev kho mob zoo rau DN kom txo tau cov teebmeem ntawm miR{18}} pawg, tom qab ER kev nyuaj siab [34]. Tsis tas li ntawd, lncRNA NEAT1 antagonism kuj yog ib qho kev kho mob, txij li NEAT1 antagonism ua rau kev tawm tsam ntawm ECM los ntawm kev txo qis ntawm ASK1, FN thiab TGF 1 ntau lawm [83]. Qhov no NEAT1- koom nrog ECM kev tawm tsam yog vim nws cuam tshuam nrog miR-27b-3p, thiab nws lub hom phiaj, TGF thiab Zeb1 [83]. Kev tswj hwm ntawm antiapoptotic lncRNA, TUG-1, suppresses miR-377 kev qhia thiab nws lub hom phiaj PPAR thiab yog li tiv thaiv ECM tsub zuj zuj hauv DN nas [42]. Yog li ntawd, kev kho mob kom nce TUG-1 kev qhia tuaj yeem ua tau zoo los kho DN phenotype thiab rov ua dua.lub raum qauv, txawm hais tias xav tau kev tshawb fawb ntxiv kom nkag siab txog nws lub peev xwm [42]. Cov kev tshawb pom no yuav tso cai rau kev txhim kho kev nkag siab ntawm kev sib cuam tshuam ntawm lncRNAs thiab lawv lub hom phiaj miRNAs, uas tuaj yeem muaj txiaj ntsig zoo rau kev xaiv lub hom phiaj los tiv thaiv ECM deposition thiab kev tswj hwm ntawm DN kev loj hlob. Daim duab 2 qhia txog LncRNAs thiab microRNAs kev sib cuam tshuam hauv kev tswj cov ntshav qab zib nephropathy
LNCs hauv Cov Cai ntawm Antifibrotic microRNAs CrosstalkTGF suppresses antifibrotic miRNAs xws li miR-29 pawg thiab miR-let-7 pawg [84]. Kev txwv tsis pub muaj TGF 1- tswj kev sib tham ntawm miRNAs tau tshaj tawm hauv cov neeg mob ntshav qab zib hom I uas muaj tus nqi siab dua ntawm ESRD kev nce qib [85]. Cov ntaub ntawv los ntawm peb lub chaw soj nstuam qhia tias pawg ntawm miR-29 tsev neeg thiab miR-cia-7 tsev neeg tau pom tias muaj kev tiv thaiv kev tiv thaiv kab mob endothelial-to-mesenchymal hloov pauv (EndMT) thiab ua kom pom kev tswj hwm ob txoj hauv kev hauv lub cev [ 86–89]. Cov kev cai bidirectional no yog qhov tseem ceeb rau endothelial cell homeostasis thiab tiv thaiv EndMT hauv ntshav qab ziblub raum[76]. Targeting EndMT yog ib qho ntawm cov kev xaiv kho mob muaj peev xwm rau kev kho mob ntshav qab zibraumfibrosis [56,58]. miR-29 pawg qhia pom qhov tsis zoo, kev tswj xyuas ob sab nrog TGF receptors [76]. miRNAs tswj cov noob qhia ntawm ib leeg ncaj qha lossis tsis ncaj. Qhov no crosstalk tshwm sim yog txuas nrog kev saib xyuas ntawm antifibrotic kev ua si nyob rau hauv lubraumthiab nws qhov kev cuam tshuam ua rau kom nrawm rau lub raum fibrosis [76]. Cov kev cuam tshuam uas tiv thaiv kev cuam tshuam ntawm crosstalk no muaj txiaj ntsig zoo hauv kev tiv thaivkab mob raum[56,{1}}]. DPP-4 inhibition qhia kev tawm tsam hauv TGF signaling-driven EndMT hauv ntshav qab ziblub raumlos ntawm kev nce miR-29 pawg [67,88]. miR-29 pawg tsom rau profibrotic molecule DPP-4, thiab nws inhibition nce qib miR-29; Yog li ntawd, DPP-4 inhibitors yog cov muaj peev xwm ua rau kev kho mob ntshav qab zib nephropathy [88].
MiR-let-7 inhibits TGF receptor 1 [90], thiab TGF -smad3 signaling tau pom tias yog ib txoj hauv kev inhibitory rau miR-29 gene qhia [84,88,91,92]; yog li ntawd, raws li kev cia siab, miR-cia-7 induces qhia ntawm miR{13}} nyob rau hauv endothelial hlwb. Lwm txoj hauv kev ntawm miR-29-linked-miR-let{17}} qhia tau piav qhia los ntawm interferon-gamma (IFN )-FGFR1 axis. miR-29 lub hom phiaj IFN- [93] thiab ntxiv mus, IFN- inhibits FGFR1. FGFR1 ua lub luag haujlwm tseem ceeb hauv kev qhia ntawm miR-cia-7 tsev neeg pawg [90]. Downregulation ntawm miR-29 pawg ua rau muaj kev nce hauv IFN- theem, uas tom qab ntawd cuam tshuam FGFR1 thiab FGFR1-txoj kev qhia ntawm miR-let-7 pawg. Qhov kev tawm tsam ntawm miR-let-7 kev qhia ua rau ua rau TGF R1 protein qhia. Ua rau TGF- / smad3 signaling, nyob rau hauv lem, inhibits kev qhia ntawm miR-29 tsev neeg pawg [88]. AcSDKP yog ib qho tseem ceeb peptide uas yog ib feem synthesized nyob rau hauv lub distal tubular cheeb tsam los ntawm lub enzymatic kev txiav txim ntawm polyoligopeptidase ntawm thymosin 4 thiab degraded los ntawm angiotensin-hloov enzyme. Yog li, angiotensin-hloov enzyme inhibitors tau pom tias nce qib ntawm AcSDKP hauv cov ntshav ntawm cov nas thiab cov neeg mob ntshav qab zib [86,89]. Ntau qhov kev tshawb fawb tau raug tshuaj xyuas rau lub raum kev tiv thaiv lub peev xwm ntawm AcSDKP thiab ACE inhibitors tuaj yeem ua cov haujlwm antifibrotic los ntawm kev nce qib AcSDKP ib nrab [70,89,94]. Qhov tseem ceeb tshaj plaws AcSDKP yog ib qho tseem ceeb endogenous peptide uas restoresraumqauv thiab suppresses lub raum fibrosis los ntawm counteracting DPP-4-sociated EndMT los ntawm elevating mimicroRNA crosstalk kev cai ntawm miR-29 thiab miR-let-7 [86]. Tsis tas li ntawd, inhibition ntawm ACE nce qib ntawm AcSDKP thiab ua rau muaj kev txhim kho ntawm cov tshuaj tiv thaiv kab mob microRNAs thiab rov ua kom cov tshuaj tiv thaiv kab mob sib tham hauv cov kab mob endothelial, thaum angiotensin receptor blockers muaj qhov cuam tshuam tsawg heev [76,{7}},89]. Cov xwm txheej no tswj kev sib txuas lus ntawm miR-29s thiab miR-cia-7s hauv fibrotic ob lub raum ntawm cov nas mob ntshav qab zib [86]. AcSDKP tuavraumhomeostasis ib nrab los ntawm kev txhawb nqa txoj cai bidirectional ntawm miR-29s thiab miR-let-7s [76,86].
Lnc-H19 qhia yog upregulated hauv TGF 2-induced endothelial hlwb thiab hauv Fifi- bioticlub raumCov kab mob ntshav qab zib mellitus [22] H19 tsub kom txo qis EndMT thiabraumfibrosis [22]. Qhov kev qhia H19 upregulated nyob rau hauv lub raum ntshav qab zib yog txuam nrog downregulated theem ntawm miR-29a [22]. H19 thiab miR-29 koom haum pab txhawb rau kev tswj hwm kev sib koom tes hauv EndMT [22]. Cov txheej txheem tswj hwm H19 zoo ib yam yav dhau los tau tshaj tawm, xws li H19 / miR675 txoj hauv kev, uas inhibits cell loj hlob thiab Igf1r qhia [95]; H19/Cia-7-mediated inhibition of HMGA2-mediated epithelial-to-mesenchymal transition [96] thiab H19/miR-675 axis inhibits prostate cancer metastasis ntawm TGF 1 [97]. Xie et al. (2016) kuj pom tias H19 kev cuam tshuam nrog miR17 tau pab txhawb rau kev tswj hwm kev sib koom tes hauv lub raum fibrosis [98]. H19 ua raws li kev sib tw endogenous RNA. Cov kev tswj hwm kev sib koom ua ke ntawm kev sib txuas lus thiab tom qab kev hloov pauv kev tswj hwm ntawm EndMT thiab lub raum fibrosis [22]. Interestingly, inhibition ntawm H19 tsuas yog hloov miR-29ib theem, tsis yog miR-29b lossis miR-29-c, thiab suppressed TGF- /Smad signaling thiaj li tswj tau EndMT thiab lub raum fibrosis hauv ntshav qab zib. [22].
LncRNA-miRNA-raws li kev kho mob rau DKD, yav tom ntej cov lus qhia thiab kev pomNtau yam tsis-coding RNAs (miRNAs, lncRNAs thiab circRNAs) tswj cov kev qhia ntawm cov noob tseem ceeb koom nrog hauv DN phenotypes. Cov non-coding RNAs (nc RNAs) no ruaj khov hauv cov kua roj ntsha thiab tuaj yeem muab cov biomarkers muaj peev xwm hauv ntau hom kab mob. Tsis-coding RNAs koom nrog hauv cov txheej txheem kab mob ntawm hypertrophy, ECM synthesis, apoptosis thiab lub raum fibrosis. Tsis tas li ntawd, qee qhov kev tshawb fawb tau nce mus rau synthesize ncRNAs-raws li kev kho mob, nrog ob peb ntawm cov ncRNAs twb nyob rau hauv kev sim tshuaj. Yog li, cov ncRNAs-raws li kev kho mob yuav yog lwm txoj hauv kev rau kev kho mob ntawm DN [99]
MiRNA-based therapeutics tuaj yeem siv los ua lwm txoj kev kho mob rau kev kho mob ntawm ntau yam kab mob xws li ntshav qab zib nephropathy. Daim ntawv thov ntawm cov khoom siv hluavtaws oligonucleotides rau kev ua haujlwm (miRNA mimics) lossis knockdown microRNAs (antagomiRs) tau hloov zuj zus [99,100]. Nyob rau hauv no series, xauv nucleic acid (LNA) inhibitor tau tsim los suppress ib qho kev qhia tshwj xeeb miRNA lossis kev ua [99,100]. Qhov zoo tshaj plaws, LNA-miR-192 kev kho mob txhim kho DN phenotype thiab yog li tuaj yeem siv los ua kev kho DN muaj peev xwm [101]. Lwm txoj haujlwm tau qhia tias kev txhaj tshuaj subcutaneous ntawm anti-miR-21 inhibited qib fibrosis nyob rau hauv ntev.mob raummus [102]. miR-29 tsev neeg txhim kho lub raum qauv thiab fibrosis yog DN nas [103], yog li kev kho mob los tiv thaiv miR-29- tuaj yeem siv los ua lwm txoj hauv kev kho DN. miRNA-raws li kev kho mob tau txais lub zog ntau dua kaum xyoo dhau los. Txawm li cas los xij, qhov teeb meem nyob hauv txoj kev xa khoom. miRNAs tswj ntau lub hom phiaj tib lub sijhawm; Yog li, lawv tuaj yeem cuam tshuam rau lwm txoj hauv kev. Yog li, kev tshawb fawb hauv miRNA-raws li kev kho mob tam sim no hloov mus rau kev tsom mus rau txoj kev xa khoom thiab kev ua tau zoo thiab kev nyab xeeb rau lub hom phiaj ib txoj hauv kev thiab cov ntaub so ntswg hauv zos [104-106].
Tsis tas li ntawd, qhov loj ntawm cov tshuaj molecule yuav tsum me me kom hla lub endothelium mus rau hauv lub cev los yog qhov chaw ntawm kev txaus siab thiab yuav tsum tsis txhob raug lim tawm los ntawm lub endothelium.raum[107]. Interestingly, qhov teeb meem pom no yog qhov zoo dua rau kev kho mob miRNA, txij li cov hlwb epithelial reabsorb cov tshuaj kho los ntawm ultrafiltrate, yog li txo qhov poob [107,108]. Yog li ntawd, nws ntseeg tau tias kev kho mob raws li miRNA tuaj yeem siv tau zoo rau DN cov ntsiab lus, txawm hais tias kev ua haujlwm siab heev lossis kev sim tshuaj loj tseem xav tau. Ntau qhov kev kho mob miRNA tau nce mus rau kev sim tshuaj, txawm tias tsis muaj rau kev kho DN. Miravirsen (LNA-based miR-122 inhibitor) twb tau nkag mus rau theem II kev sim tshuaj kho mob HCV hauv cov neeg mob [109]. Ntau yam kev kho mob miRNA yog tam sim no nyob rau hauv kev loj hlob rau ob peb lwm yam kab mob; Yog li ntawd, kev siv miRNA-raws li kev kho mob rau DN yog qhov kev cia siab tshiab. Lwm qhov kev xaiv kho tau yog lncRNAs-kho kho mob rau DN. Nws yog qhov zoo sib piv rau lub hom phiaj ntawm lncRNA kev qhia thaum piv rau miRNAs, vim tias nws lub luag haujlwm ua haujlwm hauv kev tswj xyuas cov ntaub ntawv, cov ntaub so ntswg tshwj xeeb thiab cov kab mob tshwj xeeb hloov pauv. LncRNAs feem ntau muaj nyob rau hauv lub nucleus; Synthetic antisense oligonucleotides (ASOs) tau hais dav dav kom ntsiag to lncRNA qhia hauv lub nucleus los ntawm kev pib RNase H-dependent degradation [110,111]. Kev tsim ntawm ASOs yog qhov tseem ceeb heev vim nws yuav tsum khi rau LncRNA qhov chaw tshwj xeeb thiab tsom rau ib qho lncRNA. Tsis tas li ntawd, qhov kev sib tw tiag tiag yog kho nrog ASO hauv vivo. Zoo ib yam li miRNA-raws li kev kho mob, cov teeb meem nyob hauv kev xa khoom thiab kev ua tau zoo.
CISTANCHE yuav txhim kho lub raum / raum mob
Lwm qhov teeb meem ntsig txog lncRNAs raws li kev kho mob yog qhov xwm txheej tsis sib xws thiab tsis muaj kev tiv thaiv kab mob ntawm lncRNAs [1,112]. Cov kev tshawb fawb ntxiv yog xav tau los txheeb xyuas cov molecules me me uas ua rau kev qhia ntawm lub raum tiv thaiv tsis-coding RNAs. Yuav tsum tau tshawb nrhiav cov tebchaw uas ua rau muaj kev qhia ntawm antifibrotic noncoding RNAs hauv lub raum mob ntshav qab zib, xws li flavonoids, chalcones, poly hydro quinolines, propiophenone derivatives, deoxyandrographolides, 2-methoxy-estradiol thiab thiazolidine- 4- ib qho derivatives; cov khoom siv hluavtaws lossis cov nroj tsuag-raws li cov tshuaj no tau pom muaj kev tiv thaiv hauv nas cov qauv ntawm ntshav qab zib mellitus [113–125], thiab tuaj yeem kuaj ntxiv thiab siv hauv kev tswj hwm ntawm DN. ncRNAs ua lub luag haujlwm tseem ceeb hauv cov kab mob ntawm hom II DM thiab mob ntshav qab zib mellitus; Txawm hais tias lawv cov kev txwv, cov ntaub so ntswg tshwj xeeb microRNAs qhia yuav tsum tau kawm ntxiv [56,126,127]. Lub cev tsis ua haujlwm, kev hloov pauv hauv metabolic, kev ntxhov siab thiab kev mob tshwm sim ua ntej tom qab nta xws li proteinuria, uas yog ib qho tseem ceeb rau kev loj hlob ntawm DKD [20]. Proteinuria txiav txim siab cov txiaj ntsig ntawm lub raum ntawm cov neeg mob nrog DKD [128–130]. Cov proteinuria ntau dua ua rau tubular puas tsuaj thiab cuam tshuam nrog rau lub raum o thiab interstitial fibrosis hauv ntshav qab zib [129-131]. Minutolo et al. tau kawm txog lub luag haujlwm tseem ceeb ntawm cov proteinuria hauv cov neeg mob uas muaj mob ntshav qab zibmob raum(DM-CKD), thiab sib tham txog cov ntaub ntawv tshiab ntawm kev mob plawv-lub raum hauv cov neeg mob DM-CKD [128]. Thaum tsis muaj proteinuria, DM-CKD cov neeg mob tsis muaj kev pheej hmoo ntawm lub raum mob plawv thaum piv nrog cov neeg mob uas tsis muaj ntshav qab zib CKD [128]. Txawm li cas los xij, hauv CKD cov neeg mob uas muaj proteinuria, qhov kev pheej hmoo ntawm cov kab mob hauv lub raum kawg feem ntau yog vim cov proteinuria tsis muaj ntshav qab zib [20,132]. Lub physiological thiab cellular lub luag hauj lwm ntawm kev hloov pauv ntawm microRNAs thiab lncRNAs muaj feem xyuam rau kev kawm proteinuria thiab txuam nrog DN. Tsis tas li ntawd, lncRNAs xws li GAS5 thiab GM6135, uas tau hloov kho thaum lub raum mob, yuav raug hais los ntawm Lnc-inhibitor [133,134]. Ib yam li ntawd, kev tshawb fawb txog RNAs thiab lawv lub luag haujlwm hauv kev noj qab haus huv thiab kab mob ntawm lub raum mob ntshav qab zib mellitus tau nce ntxiv. circRNA_15698, circLRP6, circACTR2, circCHIPK3, thiab circ_0000491 yog txuam nrog raum mob thiab fibrosis whereas circRNA{21}} yog reno-tiv thaiv [135–140]. Yog li ntawd, kev nkag siab zoo dua ntawm lub luag haujlwm ntawm cov kev tswj hwm RNAs nyob rau hauv lub cev ntawm ntau haiv neegraumhom cell yog xav tau. Table 1 nthuav qhia cov npe ntawm lncRNAs thiab ncig RNAs thiab lawv cov hom phiaj hauvmob raum.Lub luag haujlwm ntawm lncRNAs yuav tsum tau txheeb xyuas hauv cov chaw kho mob ua ntej siv lawv cov peev xwm kho mob hauv kev tswj cov ntshav qab zib nephropathy. Yog li, kev tshawb fawb dav dav qhia txog lub luag haujlwm ntawm miRNAs thiab LncRNAs kev sib cuam tshuam yog xav tau los ua kom muaj txiaj ntsig ntawm kev siv cov miRNAs / lncRNAs-raws li kev kho mob hauv proteinuria thiab txuam nrog DN.
Cov lus xaus miRNAs thiab lncRNAs kev sib cuam tshuam cuam tshuam rau DKD kev vam meej los ntawm kev tsom cov noob muaj feem xyuam rau fibrogenesis, ER kev nyuaj siab, o, oxidative kev nyuaj siab, thiab metabolic tsis ua hauj lwm [8,49,110]. Kev txheeb xyuas txoj hauv kev tswj hwm theem pib (lub cev tsis ua haujlwm, kev hloov pauv hauv metabolic, ER-kev ntxhov siab, thiab mob) thiab theem kawg (proteinuria) yog qhov tseem ceeb hauv kev tshawb fawb ntawm DN pathogenesis. miRNAs thiab LncRNAs kev sib cuam tshuam qhib thaj chaw dav rau kev tshawb fawb hauv paus thiab rau kev txhim kho cov kev kho tshiab tshiab tiv thaiv cov teeb meem mob ntshav qab zib suav nrog DKD.
