Lub luag hauj lwm ntawm Histone Deacetylases nyob rau hauv lub raum kev loj hlob thiab kab mob Part 1

Abstract

Histone deacetylases (HDACs)yog ib qho tseem ceeb epigenetic regulators uas kho covdeacetylationntawm ob histone thiab non-histone proteins. HDACs, tshwj xeeb tshaj yog nyob rau hauv chav kawm I HDACs, tau qhia ntau heev hauv kev tsim lub raum thiab raug tswj xyuas kev loj hlob. HDACs ua lub luag haujlwm tseem ceeb hauv kev tsim lub raum, tshwj xeeb tshaj yog nephron progenitor txij nkawm, thiab sib txawv. Ntau cov ntaub ntawv pov thawj txhawb nqa lub luag haujlwm tseem ceeb ntawm HDACs hauv kev txhim kho thiab kev loj hlob ntawm ntau yam kab mob raum. HDAC inhibitors (HDACis) muaj txiaj ntsig zoo hauv kev tiv thaiv thiab kho kab mob raum (xws li mob qog noj ntshav raum). Kev nkag siab zoo dua ntawm cov txheej txheem molecular hauv qab lub luag haujlwm ntawm HDACs hauv cov kab mob thiab kev loj hlob ntawm lub raum kab mob zoo li yuav muaj txiaj ntsig zoo hauv kev txhim kho cov txiaj ntsig zoo thiab tsis tshua muaj tshuaj lom HDAC inhibitors thiab combinatorial therapeutics.

Ntsiab lus

Histone deacetylases · Histone deacetylase inhibitors · raum kab mob · raum mob cancer

Taw qhia

Epigenetics xa mus rau kev kawm txog kev hloov pauv ntawm cov noob caj noob ces thiab kev tswj hwm ntawm nws tus kheej ntawm DNA ib ntus. Xyoo tsis ntev los no tau pom muaj kev paub txog lub luag haujlwm tseem ceeb ntawm cov txheej txheem epigenetic hauv kev noj qab haus huv thiab kab mob [1]. Thaum lub sij hawm txoj kev loj hlob, kev hloov kho epigenetic, xws li DNA methylation, histone acetylation, thiab histone methylation, yog teem rau hauv chromatin los txiav txim siab lub genome programming nyob rau hauv ib lub cell los ntawm kev hloov ntawm chromatin qauv thiab yog li DNA nkag tau mus rau lub transcriptional machinery. Kev cuam tshuam ntawm cov kev hloov pauv ntawm epigenetic uas tshwm sim los ntawm ib puag ncig cuam tshuam (xws li kev noj zaub mov, co toxins, tshuaj, kab mob kis kab mob) tuaj yeem ua rau muaj kev ua haujlwm tsis zoo ntawm cov noob caj noob ces, yam tsis tau hloov pauv DNA ntu nws tus kheej [1-3]. Raws li epigenetic txawv txav nyob ntawm qhov sib cuam tshuam ntawm cov noob thiab ib puag ncig, lawv feem ntau phenotypically variable, uas haum zoo nrog lub dav phenotypic spectrum ntawm congenital anomalies ntawm lub raum thiab urinary tract (CAKUT) thiab lwm yam kab mob raum [4-9]. Yog li ntawd, nkag siab lub hauv paus epigenetic ntawmraumtxoj kev loj hlob tuaj yeem muab kev nkag siab tshiab rau hauv cov txheej txheem pathological ntawm lub raum thiab, cia siab tias, qhib txoj hauv kev tshiab rau kev kho lossis tiv thaiv CAKUT, los ntawm cov kws tshuaj uas tsom mus rau kev hloov pauv ntawm epigenetic. Xws li cov tshuaj epigenetic twb nyob rau hauv kev kho mob siv los yog nyob rau hauv kev tshawb nrhiav rau kev kho mob ntawm cancer nrog rau lwm yam kab mob [10].

Histone acetylation ua rau covalent ntxiv ntawm ib pawg acetyl mus rau lysine. Xws li ib qho ntxiv ua rau hauv zos qhib chromatin, ib qho cim ntawm kev hloov pauv hloov pauv, los ntawm kev cuam tshuam cov txiaj ntsig zoo ntawm histone tus Tsov tus tw thiab txo nws txoj kev khi rau DNA tsis zoo. Hauv qhov sib piv, deacetylated histones cuam tshuam nrog DNA thiab ua rau hauv zos ze chromatin, ib qho cim ntawm kev tsis ua haujlwm. Differential acetylation ntawm kev txhawb nqa thiab txhim kho histones plays lub luag haujlwm tseem ceeb hauv kev tswj hwm kev loj hlob, cellular proliferation, thiab sib txawv. Aberrant acetylation lossis deacetylation ua rau muaj ntau yam kab mob xws li leukemia, qog nqaij hlav epithelial, fragile X syndrome, thiab Rubinstein-Taybi syndrome [11]. Histone deacetylases (HDACs) yog ib tsev neeg loj ntawm evolutionarily conserved enzymes uas catalyze tshem tawm cov acetyl pawg los ntawm histone tails. Qhov kev txiav txim ntawm HDACs yog counteracted los ntawm histone acetyltransferases (HATs), uas acetylate histone tails. Txog tam sim no, 18 tsiaj txhuHDACstau raug txheeb xyuas. Raws li kev txheeb xyuas phylogenetic thiab lawv txoj haujlwm, HDACs tau muab faib ua plaub chav kawm: chav kawm 1 (Hdac1-3, thiab 8), chav kawm II (Hdac4-7, 9–10), chav kawm III (Sir2/Sirt 1). -7), thiab chav kawm IV (Hdac11). Chav kawm I, II, thiab IV xav tau zinc rau lawv cov kev ua haujlwm catalyze, thaum cov tswv cuab hauv chav kawm III vam khom NAD rau kev ua si. Ntawm lawv, chav kawm I HDACs tau kawm ntau yam thiab ua tau zoo. Muab hais tias histone acetylation feem ntau cuam tshuam nrog kev hloov pauv hloov pauv, HDACs yog thawj zaug suav tias yog cov kev hloov pauv dav dav. Txawm li cas los xij, tom qab ntawd, nws tau dhau los ua qhov tseeb tias HDACs tswj cov noob qhia hauv txoj kev xaiv tau zoo thiab nthuav tawm ob qho kev tawm tsam thiab ua kom muaj zog [12]. Vim tias tsis muaj qhov sib xyaw ua ke ntawm DNA ua haujlwm,HDACstsis tuaj yeem ua haujlwm ib leeg rau lawv txoj haujlwm hauv ntau yam txheej txheem lom neeg [12].

Nyob rau hauv xyoo tas los no, kev tshawb fawb txog kev siv cov qia hlwb thiab cov tshuaj suav tshuaj ntsuab rau kev kho mob ntawmkab mob raumtau txais txiaj ntsig zoo. Lub ntsiab mechanism ntawm ob txoj kev kho mob yog los txhawb kev kho cov mob raum cov ntaub so ntswg thiab tiv thaiv lub raum tshuav nyiaj li cas.

Suav tshuaj ntsuab kho mob,cistanche, tau siv hauv tshuaj suav tshuaj los kho ntau yammob raum mobtxij thaum ub los. Nws tau tshaj tawm tias cistanche muaj peev xwm txo qhov mob,txo lub raum fibrosis, thiab txhawb cov synthesis ntawm extracellular matrix Cheebtsam. Nws tau raug tshaj tawm tias cov teebmeem no yog vim nws cov khoom siv bioactive, suav nrog ntau cov tshuaj phenolic, triterpenoids, thiab coumarins.

Ntawm qhov tod tes, stem cell technology tau ua rau muaj kev hloov pauv hauv kev kho mob. Kev tshawb fawb tau pom tias cov qia hlwb tuaj yeem sib txawv rau hauvntau hom raum hlwbthiab ua cov haujlwm kho mob, suav nrog kev tiv thaiv cov ntaub so ntswg raum ua haujlwm, ua kom cov nqaij mos fibrosis, thiab kho cov ntaub so ntswg puas.

Thaum kawg, kev sib xyaw ntawm cov tshuaj suav tshuaj suav nrog kev tshawb fawb niaj hnub tuaj yeem yog tus yuam sij rau kev kho ntau yamkab mob raum. Cov tswv yim no tau maj mam lees txais los ntawm cov neeg kho mob thiab cov kev tshawb fawb tau pom tias kev kho mob ua ke ntawm cistanche thiab qia cell kho yuav txo tau qhov kev tuag ntawm cov neeg tuag.kab mob raum. 

Hauv kev xaus, kev siv ntawmcistanchethiab qia cell kho hauv kev kho mob ntawmkab mob raumqhia tau hais tias muaj peev xwm zoo thiab xav tau kev tshawb fawb ntxiv. Kev sib xyaw ua ke ntawm ob txoj kev kho mob tuaj yeem muab kev kho mob zoo dua rau cov neeg uas ntsib cov kab mob raum.

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Nws tau dhau los ua qhov tseebHDACstuaj yeem ua rau ntau lub substrates ntxiv rau histones. Nws yog qhov nyuaj los txiav txim siab qhov histone substrate tshwj xeeb ntawm HDACs sib txawv. Lub ntsiab yog vim li cas ntau purifiedHDACsmuaj kev ua haujlwm deacetylation tsawg heev thiab ua haujlwm rov ua haujlwm ntawm HDACs sib txawv [13]. Qhov poob lossis poob ntawm ib tus tswv cuab ntawm HDACs yuav tsis txaus los hloov tag nrho histone acetylation. Tsis tas li ntawd, HDACs raug xaiv los tsom cov noob los ntawm kev koom tes nrog cov kev hloov pauv (xws li Sin3 complex, NuRD complex, thiab Co-REST complex) [14]. Yog li, qhov tshwj xeeb ntawm HDACs hauv kev tswj hwm noob nyob ntawm tus khub cov proteins uas lawv koom nrog ntau hom cell. Txawm hais tias peb tus tswv cuab ntawm chav kawm I HDACs (HDAC1, HDAC2, thiab HDAC3) feem ntau qhia cov yam ntxwv zoo sib xws, qee qhov kev tshawb fawb pom tias HDAC3 (thiab tej zaum tag nrho cov chav kawm I HDACs) muaj qhov sib txawv substrate tshwj xeeb [15, 16]. Qhov zoo tshaj plaws, txhua HDAC muaj nws cov phiaj xwm tshwj xeeb hauv qee qhov substrates, uas yuav tsum tau tshawb xyuas ntau dua. Zoo li yuav luag tag nrho cov enzymes, HDACs tau tswj hwm lawv cov dej num. Ntawm ntau cov txheej txheem kev tswj hwm ntawm ntau qib, protein-protein kev sib cuam tshuam thiab kev hloov pauv tom qab (PTMs) yog ob txoj kev pub noj zoo. Ntau HDACs tsis ua haujlwm ib leeg tab sis ua raws li cov khoom siv hauv ntau cov protein ntau, uas pab cov HDACs rau tib neeg kom siv lawv cov kev ua haujlwm catalytic hauv kev ua tau zoo thiab tshwj xeeb [17]. Nws yog ntau heev rau HDACs ua haujlwm los ntawm kev tsim cov protein ntau ntau. Kev txheeb xyuas biochemical dav dav pom tau tias HDAC1 thiab HDAC2 sib koom ua ke nyob rau hauv peb qhov loj multiprotein co-repressor complexes: Sin3, NuRD (nucleosome remodeling thiab deacetylation), thiab CoREST (co-repressor rau lub ntsiab-1-silenced transcription factor) [14] . HDACs tsis yog tsuas yog hloov pauv cov protein, lawv tuaj yeem ua rau ntau yam PTMs. Phosphorylation yog qhov kev tshawb nrhiav dav dav tshaj plaws. HDAC1 tuaj yeem ua phosphorylated los ntawm casein kinase (CK2) thiab cAMP-dependent kinase PKA [18]. Phosphorylation ntawm ob qho tib si Serine (S) 421 thiab S423 yog qhov tseem ceeb rau kev ua haujlwm enzymatic ntawm HDAC1, thiab kev hloov pauv ntawm ob qhov chaw no txo ​​nws txoj kev ua haujlwm thiab kev tsim tawm. CK2 tseem tuaj yeem phosphorylate HDAC2 ntawm qhov chaw 422 thiab 424 (homologs rau S421 thiab S423 ntawm HDAC1), thiab ntawm S394, qhov chaw phosphorylation tseem ceeb ntawm HDAC2 [19]. Tsis tas li ntawd, peb kuj pom muaj S394 phosphorylated Hdac2 nyob rau hauv lub raum kev loj hlob ntawm loj spectrometry tsom xam (Liu li al., unpublished). Tsis tas li ntawd, phosphorylation ntawm HDAC1 thiab HDAC2 yog reversibly tswj los ntawm cov protein phosphatase PP1 [20]. Cov kev tshawb fawb kuj tau qhia tias PP2A tswj cov lus teb hypertrophic los ntawm dephosphorylating S394 ntawm HDAC2 hauv tib neeg lub siab [21]. Sib sau ua ke, HDACs yog qhov tseem ceeb ntawm cov txheej txheem epigenetic modulators thiab ua lub luag haujlwm hauv ntau cov txheej txheem lom neeg. Lawv cov dej num tau nruj tswj hwm los ntawm ntau lub tswv yim, xws li kev sib cuam tshuam ntawm cov protein-protein, thiab PTMs. Kev tsim cov txheej txheem multiprotein txiav txim siab tsis yog tsuas yog kev ua haujlwm ntawm HDACs xwb tab sis kuj yog lawv cov substrate tshwj xeeb. Cov kev hloov pauv molecular los ntawm HDACs yuav muaj feem cuam tshuam rau tib neeg kev noj qab haus huv thiab kab mob. Hauv kev tshuaj xyuas no, peb xav piav qhia txog lub luag haujlwm ntawm HDACs hauv lub raum kev loj hlob thiab kab mob.

Lub luag haujlwm ntawm HDACs hauv lub raum kev loj hlob

Qhov kev nthuav qhia thoob plaws thiab kev ua haujlwm siab deacetylase ntawm chav kawm I HDAC yog ua raws li lawv qhov tseem ceeb. HDAC1 cov nas uas muaj suab npe nrov yog embryonic tuag, uas ua rau muaj kev loj hlob tsis zoo thiab kev loj hlob qeeb [22]. Kuj ceeb tias, qhov kev txiav txim siab ntawm HDAC1 tau txais txiaj ntsig zoo hauv ntau cov ntaub so ntswg thiab cov nas tuaj yeem siv tau, feem ntau yog vim muaj kev ua haujlwm tsis zoo ntawm HDAC1 thiab HDAC2 hauv kev txhim kho tom qab thiab tom qab lub neej [22]. Kev sib koom ua ke ntawm HDAC 1 thiab HDAC2 yog kev puas tsuaj rau tag nrho cov ntaub so ntswg kuaj [22]. Ntxiv mus, HDAC2-null nas tuag tom qab yug los hauv 24 teev vim lub plawv tsis ua haujlwm [22]. Hauv lub raum,HDACsyog ubiquitously thiab nthuav heev. RT-PCR tsom xam qhia tias HDAC1, 2, 3, 4, 7, thiab 9 yog raug rau kev loj hlob tswj thiab poob qis heev thaum lub sij hawm maturation ntawm embryonic mus rau neonatal thiab neeg laus lub neej [23]. Western blot tsom xam ntawm lub raum nuclear lysates ntxiv kev lees paub tias Hdac1-3 proteins muaj ntau heev nyob rau hauv lub raum embryonic thiab yog down-regulated postnatally [23]. Immunostaining qhia tau hais tias Hdac 1 thiab 2 tau qhia ntau heev nyob rau hauv ntau haiv neeg ntawm lub raum tsim nyob rau hauv lub raum ntawm yug tshiab (P0) nas, nrog rau cov undifferentiated metanephric mesenchyme, branching ureteric buds, thiab stroma (Fig. 1). ). Hdac1 thiab 2 yog overlappingly thiab tshwj xeeb tshaj yog nyob rau hauv nuclear qhia nyob rau hauv kev loj hlob thiab P21 ob lub raum (Fig. 1). Kev qhia siab ntawm Hdac3 kuj tau kuaj pom hauv kev tsim lub raum, suav nrog podocytes. Los ntawm qhov sib piv, Hdac 5, 6, thiab 8 yog constitutively qhia. Lub raum microvasculature qhia Hdac 7, 8, thiab 9 [24]. Ua ke, chav kawm I thiab chav kawm II HDAC cov noob tau sib txawv raws li kev tswj hwm thaum lub sijhawmkev loj hlob ntawm lub raum. Kev nthuav qhia ntawm tag nrho covHDACsnyob rau hauv lub raum tau zoo sau tseg los ntawm kev tshuaj xyuas tsis ntev los no [25]. Txawm li cas los xij, spatially thiab ib ntus txwv kev faib tawm ntawmHDACstsis hloov lub ntiaj teb no acetylation theem ntawm histones H3 thiab H4, tawm tswv yim nruj coupling ntawm HAT thiab HDAC zog thaum lub sij hawm ib txwm kev loj hlob [23].

Ntawm cov hoob kawm I HDACs, HDAC1 thiab HDAC2 yog evolutionarily muaj feem xyuam rau ib leeg thiab ob leeg muaj abundantly qhia nyob rau hauv ntau cov ntaub so ntswg. HDAC1 thiab HDAC2 tuaj yeem tsim homo- lossis heterodimers thiab pom ua ke nyob rau hauv yuav luag tag nrho cov nuclear protein complexes, nrog rau peb qhov zoo-tus cwj pwm co-repressor complexes: Sin3, NuRD, thiab Co-REST [14, 26]. Los ntawm kev tshem tawm Hdac1 thiab Hdac2 nyob rau hauv ureteric bud (UB) kab mob nrog Hoxb7-Cre, cov kev tshawb fawb tau qhia tias nas uas tsis muaj ntau tshaj li peb tshem tawm alleles ntawm Hdac1 thiab Hdac2 pom tsis muaj qhov txawv txav hauv lub raum [27]. Cov nas no tuaj yeem muaj sia nyob mus rau cov neeg laus yam tsis muaj qhov txawv txav hauv kev loj hlob lossis kev loj hlob. Los ntawm qhov sib txawv, kev rho tawm ib txhij ntawm tag nrho plaub alleles ntawm Hdac1 thiab Hdac2 ua rau muaj kev tuag ntxov tom qab yug menyuam los ntawm 2-4 lub lis piam ntawm hnub nyoog [27]. Lub raum cov ntaub so ntswg ntawm knockout nas ntawm P0 tau qhia tias tsis muaj ib cheeb tsam nephrogenic, tsis muaj cortical-medullary qauv, thiab tsim ntawm ntau cov kab mob epithelial, qhia txog lub luag haujlwm tseem ceeb thiab ua haujlwm rov ua haujlwm ntawm Hdac1 thiab Hdac2 hauv lub raum tsim. thiab ua haujlwm [27]. Cov kev tshawb fawb kuj qhia tau hais tias kev poob ntawm Hdac1 thiab Hdac2 hauv UB epithelium ua rau pom qhov hyperacetylation ntawm cov qog suppressor protein p53 los txhawb p53 stability thiab kev ua haujlwm transcriptional [27]. Thaum p53 yog ib qho tseem ceeb heev cov qog suppressor, unconstrained p53 kev ua si yog detrimental rau lub raum tsim, feem ntau yuav yog vim tsis tsim nyog cellular tuag los yog proliferation defects [28].

Lub raum muaj ntau hom cell tshwj xeeb nrog rau hauv cheeb tsam physiological functions. Lub raum tsim hauv cov tsiaj yog pib los ntawm kev sib cuam tshuam ntawm ob hom ntaub so ntswg, lub ureteric bud thiab metanephric mesenchyme [5, 29–31]. Lub Six2 plus cap mesenchyme yog ib qho kev rov ua dua tshiab ntawm tus kheej nephron progenitor cell (NPCs) uas ua rau muaj kev ua haujlwm nephron epithelium [30]. Txhawm rau kom nkag siab txog lub luag haujlwm ntawm HDAC1/2 hauv NPC kev saib xyuas thiab kev sib txawv, peb tau muab tshem tawm Hdac1 thiab Hdac2 nrog Six2eGFPCre (Six2TGC) nas [30]. Cov nas uas muaj NPC tshwj xeeb ob qhov kev tshem tawm ntawm HDAC1 thiab HDAC2 (tag nrho plaub alleles) tau yug los hauv qhov sib piv ntawm Mendelian tab sis tuag sai tom qab yug me nyuam [4]. Lub raum mutant tom qab yug me nyuam (P) 0 pom lub raum me me, tsis muaj nephrogenic cheeb tsam, tsis muaj nascent nephrons thiab glomeruli, thiab tsim ntau lub hlwv [4]. Zoo ib yam li Hdac1 thiab Hdac2 tshem tawm hauv UB kab mob, ib qho allele ntawm HDAC1 lossis HDAC2 yog txaus los xyuas kom meej nephrogenesis [4]. Peb cov txiaj ntsig tau pom tias histone deacetylases 1 thiab 2 (HDAC1/2) yog qhov tseem ceeb los tswj cov kev hloov pauv ntawm nephron progenitors thiab lub raum vesicles [4]. HDAC1/2 ua si ob lub luag haujlwm kom sib npaug ntawm tus kheej rov ua dua tshiab thiab sib txawv ntawm NPC thaum lub sijhawm nephrogenesis (Daim duab 2): Ntawm ib sab, HDAC1/2 yuav tsum muaj rau kev qhia ntawm tag nrho cov cim cim (xws li Six2, Sall1, thiab Osr1) hauv NPC thiab kev rov ua nws tus kheej ntawm cov hlwb no; ntawm qhov tod tes, lawv kuj tseem ceeb heev rau kev tawm tsam qhov kev qhia ntawm canonical Wnt hom noob noob thiab tiv thaiv NPCs los ntawm kev sib txawv ua ntej. Peb cov kev tshawb fawb biochemical thiab Chip kuj tau qhia tias HDAC1 thiab HDAC2 cuam tshuam nrog rau Six2, Osr1, thiab Sall1, lub network ntawm cov tswj hwm kev hloov pauv uas tswj hwm qhov sib npaug ntawm NPC proliferation thiab sib txawv [4]. Six2 yog qhov tseem ceeb ntawm kev hloov pauv hauv lub raum tsim thiab ua lub luag haujlwm tseem ceeb hauv kev tswj hwm lub luag haujlwm ntawm kev rov ua haujlwm ntawm tus kheej, los ntawm kev tawm tsam NPCs sib txawv thiab tsav tsheb rov ua dua tus kheej. Rau 2 thiab HDAC1/2 yog sib koom ua ke hauv cov NPCs tsis sib xws thiab txhua yam yuav tsum tau ua rau kev saib xyuas ntawm nephron progenitor cells thiab kev tiv thaiv kev sib txawv ntxov ntxov [4]. Peb yog vim li cas HDAC1/2 yuav tsum tau rau Six2's dual muaj nuj nqi kom meej tswj tus kheej-renewal thiab sib txawv ntawm NPCs.HDACstuaj yeem deacetylate tsis tsuas yog histone proteins tab sis kuj tsis-histone proteins [12]. Qhov kev kwv yees hauv silico los ntawm acetylation set enrichment-based (ASEB) computer program [32] qhia ntau qhov chaw muaj feem xyuam rau Six2 acetylation los ntawm p300 thiab deacetylation los ntawm Hdac1/2 (Table 1). Ntawm lawv, Lysine (K) 46, K52, thiab K71 nyob ntawm Six domain (1–124) ntawm Six2, thiab K138 nyob ntawm homeodomain ntawm Six2 [33]. Cov kev tshawb fawb pom tau hais tias Six domain muaj qhov muaj zog ntau dua rau nucleus tsub zuj zuj thiab cov protein uas muaj rau Six domain thiab homeodomain tau pom tias tsuas yog nyob rau hauv lub nucleus [33]. Yog li ntawd, acetylation ntawm cov chaw muaj peev xwm no yuav muaj feem cuam tshuam nrog cov nucleus localization ntawm Six2 protein thiab / lossis kev ua haujlwm transcriptional. Tsis ntev los no, peb qhov kev tshuaj ntsuam genome-wide pom tias Hdac1 thiab Six2 koom ua ke ntawm thaj chaw txhim kho ntawm NPC txuas ntxiv cov noob, thiab kev sib txuas ntawm Hdac1 qhia tias qhib chromatin ntawm thaj tsam txhawb nqa ntawm cov noob caj noob ces hauv NPC [34]. Yuav ua li cas HDAC1/2 tswj Six2 muaj nuj nqi rau lub raum kev loj hlob warrants ntxiv kev tshawb nrhiav.

Lub raum mammalian tsim los ntawm kev sib cuam tshuam ntawm metanephric mesenchyme thiab ureteric bud. Lub stroma, tus thib peb kab uas sau rau hauv qhov chaw interstitial, yog muab los ntawm cov progenitors txawv uas qhia txog qhov transcription factor Foxd1 [35]. Cov kev tshawb fawb pom tau hais tias Foxd1 qhia txog cortical stroma yog cov neeg muaj peev xwm rov ua dua tshiab rau tus kheej, uas yuav ua rau cov hlwb cortical thiab medullary interstitial, mesangial hlwb, thiab pericytes ntawm lub raum [35]. HDAC1 thiab HDAC2 kuj tau hais ntau dua hauv stroma ntawm kev tsim cov raum [4, 23, 27]. Txhawm rau tshuaj xyuas lub luag haujlwm ntawm ob HDACs hauv stroma kab, peb tab tom ntiav tus qauv nas kom tshem tawm HDAC1 thiab HDAC2 nrog Foxd1-Cre [36]. Peb cov txiaj ntsig ua ntej tau pom tias qhov tshwj xeeb HDAC1/2 tshem tawm hauv stromal progenitors ua rau muaj kev nthuav dav ntawm nephron progenitors (Fig. 3), qhov zoo sib xws phenotype pom hauv Foxd1-Cre driven Sall1 deletion lossis ablation ntawm lub raum stroma [37, 38] ib. Ntxiv cov yam ntxwv ntawm yuav ua li cas stromal HDAC1/2 txwv thiab tswj kev nthuav dav nephron ntau dhau yuav pab txhawb peb txoj kev nkag siab ntawm epi genetic tswj ntawm lub raum tsim thiab kev sib tham ntawm stromal thiab nephron.

HDACs thiab lub raum interstitial fibrosis

Mob raum mob (CKD) yog ib qho teeb meem kev noj qab haus huv uas tau lees paub rau pej xeem thiab raug cim los ntawm kev maj mam poob qis hauv lub raum tsis ua haujlwm. Lub raum interstitial fibrosis yog ib qho cim ntawm CKD. Lub raum interstitial fibrosis yog tus cwj pwm los ntawm lub raum tubular atrophy, txawv txav ntawm extracellular matrix (ECM), thiab kev nthuav dav ntawm fibroblasts. Lub hauv paus pathogenic mechanisms yog complex thiab ntau haiv neeg. Cov ntaub ntawv pov thawj tau pom tias HDACs koom nrog cov kab mob ntawm lub raum interstitial fibrosis thiab HDAC inhibition tawm tsam cov teebmeem hauv qab no: (1) inhibiting pro-fibrotic TGF- signaling, (2) tiv thaiv tubular epithelial cell apoptosis, thiab (3) nce kev qhia ntawm pob txha morphogenesis protein 7 (BMP7) [39]. Transforming growth factor beta (TGF-) yog ib tug tswv cuab ntawm kev hloov pauv kev loj hlob, uas yog qhov tseem ceeb hauv kev tswj hwm ntawm ntau yam txheej txheem lom neeg. Hauv cov tsiaj nyeg, peb lub isoforms ntawm TGF- tau raug txheeb xyuas hauv lub raum: TGF- 1, TGF- 2, thiab TGF- 3. Ntawm lawv, TGF- 1 exerts nws biological kev ua si los ntawm Smad thiab non-Smad txoj kev thiab nws lub luag hauj lwm nyob rau hauv lub raum fibrosis yog qhov zoo tshaj plaws yam ntxwv (Yu et al. 2003; Meng et al. 2016). Aberrant activation ntawm TGF- 1 nyob rau hauv lub raum ua rau interstitial fibrosis los ntawm kev txhawb fibroblast proliferation thiab deposition ntawm txawv txav extracellular matrix [40]. Cov kev tshawb fawb yav dhau los pom tau hais tias kev kho mob nrog trichostatin A (TSA), lub lauj kaub HDAC inhibitor (HDACi) rau ob chav kawm I thiab chav kawm II HDACs, txo qis rau lub raum fibrosis hauv unilateral ureteral obstruction (UUO) nas qauv [41]. Kev kho TSA kuj tseem ua rau tsis muaj zog fibroblasts. Ntxiv mus, kev ntsiag to ntawm HDAC1 los yog HDAC2 thaiv lub raum fibroblast proliferation los ntawm kev txo phosphorylation ntawm STAT3 (cim transducer thiab activator ntawm transcription 3), ib tug signaling molecule txuam nrog rau proliferation ntawm lub raum fibroblasts thiab kev loj hlob ntawm lub raum fibrosis [42]. Cov kev tshawb fawb ntxiv tau pom tias kev kho TSA kuj txhawb nqa kev qhia ntawm BMP-7 thiab txo cov kab mob ntawm lub raum raug mob [43, 44]. Raws li BMP-7 induces tiv thaiv TGF- - nruab nrab lub raum fibrosis, restoration ntawm BMP-7 qhia sawv cev rau lwm yam tseem ceeb mechanism uas HDAC inhibition tiv thaiv kev loj hlob CKD [44]. Tsis tas li ntawd, kev tswj hwm ntawm MS-275 lossis Fk228 (kev xaiv inhibitors ntawm chav kawm I HDACs) ua rau txo qis kev loj hlob ntawm lub raum fibrosis los ntawm inhibiting lub raum fibroblast activation thiab proliferation, qhia tias chav kawm I HDACs ua lub luag haujlwm tseem ceeb hauv lub raum fibrosis [45, 46] ib.

HDACs thiab mob ntshav qab zib raum

Mob ntshav qab zibcuam ​​tshuam ntau dua 451 lab tus tib neeg hauv ntiaj teb thiab mob ntshav qab zib nephropathy (DN, kab mob raum hauv ntshav qab zib) yog qhov ua rau CKD feem ntau. Kab mob raum kawg (ESKD) yog theem kawg ntawmCKD. Qhov no yog thaum ob lub raum tsis tuaj yeem txhawb lub cev qhov kev xav tau rau lub neej niaj hnub. Feem ntau ua rau ESRD hauv Tebchaws Meskas yog ntshav qab zib thiab ntshav siab [47]. Kev nce qib ntawm ECM hauv glomerular mesangium thiab tubulointerstitium yog qhov cim ntawm DN. Ntau qhov kev tshawb fawb preclinical tau pom qhov ua tau zoo ntawm HDAC inhibition hauv kev sim ua qauv ntawm cov kab mob raum mob ntshav qab zib [48, 49]. Cov kev tshawb fawb thaum ntxov tau tshaj tawm txog qhov nce ntawm HDAC2 kev ua haujlwm hauv streptozotocin (STZ)-vim mob ntshav qab zib raum thiab nas lub raum proximal tubular epithelial hlwb (NRK-52E) raug rau TGF- 1 [50]. siRNA knockdown ntawm HDAC2 txo qhov kev qhia ntawm fibronectin thiab -SMA hauv NRK-52E hlwb. Kev kho TSA txo qis kev qhia ntawm ECM cov khoom thiab tiv thaiv epithelial-mesenchymal-transition (EMT). Valproic acid (VPA) (lwm tus HDACI/II inhibitor) lossis SK704 (xaiv chav kawm I HDAC inhibitor) tau pom tias muaj kev cuam tshuam zoo sib xws ntawm NRK-52E hlwb, uas txhawb nqa lub luag haujlwm tseem ceeb ntawm chav kawm I HDACs hauv kev txhim kho ntawm Mob ntshav qab zib mellitus [50]

Endoplasmic reticulum (ER) kev ntxhov siab tshwm sim los ntawm reactive oxygen hom (ROS) yog txuam nrog DN txoj kev loj hlob [51]. Epidermal growth factor receptor (EGFR) mediates oxidative stress thiab EGFR activation tau cuam tshuam rau cov nas mob ntshav qab zib. EGFR / AKT / ROS / ER qhov teeb meem kev ntxhov siab plays lub luag haujlwm tseem ceeb hauv DN kev nce qib thiab inhibiting EGFR tuaj yeem ua lub peev xwm kho tau zoo hauv DN [51]. Cov kev tshawb fawb pom tau hais tias kev kho mob ntawm cov nas mob ntshav qab zib nrog vorinostat rau 4 lub lis piam txo qis EGFR qib thiab ua rau lub raum loj hlob thiab glomerular hypertrophy, qhia tias HDACs tuaj yeem ua lub luag haujlwm hauv DN thaum ntxov ntawm EGFR ua kom [48].

Cov podocytes yog qhov sib txawv ntawm cov hlwb epithelial thiab nthuav tawm ib qho tseem ceeb ntawm lub raum pom teeb meem [52]. Podocyte kev puas tsuaj ua rau kom qhov kev loj hlob ntawm DN los ntawm kev poob ntawm lub raum pom teeb meem kev ncaj ncees, ua rau kev khiav tawm ntawm cov protein mus rau cov zis (proteinuria) [52]. Nrog rau kev txheeb xyuas cov ntaub ntawv, kev ua haujlwm siab dua HDAC1 thiab HDAC2 tau kuaj pom hauv microarray los ntawm glomeruli ntawm cov nas proteinuric (Inoue li al. 2019). Cov kev tshawb fawb tsis ntev los no tau qhia txog lub luag haujlwm tseem ceeb ntawm podocyte HDAC kev ua haujlwm hauv kev tswj hwm ntawm murine thiab tib neeg cov kab mob glomerular, thiab qhia tau hais tias inhibition ntawm HDAC1 thiab HDAC2 kev ua ub no tuaj yeem cuam tshuam kev loj hlob ntawm tib neeg cov proteinuric.kab mob raum.Kev tswj hwm ntawm VPA (ib chav kawm I HDAC inhibitor, tshuaj FDA pom zoo) thiab suberanilohydroxamic acid (SAHA) txo cov proteinuria thiab txo cov kev loj hlob ntawm glomerulosclerosis hauv ntau cov nas glomerular raug mob qauv. Podocye-specific HDAC1 thiab HDAC2 ablation nas tau tiv taus cov kab mob glomerulosclerosis. Tsis tas li ntawd, kev soj ntsuam ntev ntev ntawm 120,000 cov neeg koom nrog hauv Kev Tshawb Fawb Cov Neeg Laus Laus tau pom tias muaj kev tiv thaiv zoo ntawm kev kho VPA ntawm kev poob qis ntawm qhov kwv yees glomerular pom tus nqi [52].

Hauv cov ntsiab lus,mob raumsevimntshav qab zibtseem yog feem ntau ua rau mob raum tsis ua haujlwm, thiab HDACi muab cov txiaj ntsig kho mob rau kev kho mob raum mob ntshav qab zib.

Nug ntau ntxiv: david.deng@wecistanche.com WhatApp:86 13632399501