Dichotomous Responses To Chronic Fetal Hypoxia Lead To A Predetermined Aging Phenotype Ⅱ
Nov 29, 2023
Hypoxic
Fetal raum
Qhia txog Deregulated Protein Expression Profile Kom paub meej txog txoj hauv kev molecular uas underlie hypoxia-driven IUGR, tshiab lub raum cais tawm ntawm hypoxic lossis normoxic E18.5 fetuses raug rau hauv qab-up proteome profile siv nano-LC system (Dionex UltiMate 3{{9 }}00 RSLC) ua ke nrog lub siab daws teeb meem orbitrap mass spectrometer (Thermo QExactive). Kev tsom xam cov ntsiab lus tseem ceeb tau pom qhov sib txawv ntawm lub raum hypoxic thiab normoxic (Fig. 2A). Nyob rau hauv tag nrho, 6307 proteins tau txheeb xyuas (FDR < 0.01, ntxiv Table S2) uas 436 tau deregulated loj (FDR < 0.05); 284 nrog nce abundance thiab 152 nrog txo abundance. Functional annotation pawg siv cov noob ontology (18–20) qhia txog kev txhawb nqa ntawm cov mitochondrial, lysosomal, RNA-, thiab DNA-binding proteins, nrog rau cov proteins koom nrog hauv cov txheej txheem metabolic tshwj xeeb lossis cov lus teb hauv lub cev tsis muaj zog (Fig. 2, B–D) . Peb categorized cov proteins no hais txog (1) nephron tsim, (2) metabolic adaptation, thiab (3) ceev aging, raws li tau hais thiab tham nyob rau hauv cov nqe lus hauv qab no.
Repressed DNA Replication thiab Protein Synthesis Pab txhawb kev tsim cov Nephrons tshiab hauv Chronic Hypoxia
Cov xwm txheej tsis zoo thaum lub sij hawm kev loj hlob xws li mob fetal hypoxia tau nquag pom muaj feem cuam tshuam nrog cov lej nephron (27, 29-32). Txawm li cas los xij, lub hauv paus txheej txheem ua kom ntseeg tau piav qhia qhov kev tshawb pom no tsis tshua muaj tshwm sim. Clustering tag nrho 64 deregulated proteins teej tug mus rau GO-cov ntsiab lus "DNA-binding" thiab "RNA-binding" (a heatmap yog qhia nyob rau hauv supplemental Fig. S2) siv STRING database (22) qhia ntau subnetworks nrog rau DNA kho, DNA replication, mRNA splicing, thiab ribosomal proteins (Fig. 3A). Ib daim ntawv teev ntau ntxiv ntawm cov txheej txheem los yog txoj hauv kev muaj nyob hauv daim duab 3B (FDR < 0.05). Ntawm cov "Ribosome" thiab "DNA replication" yog ib qho ntawm cov ntsiab lus saum toj kawg nkaus ntawm repressed proteins, whereas mRNA splicing thiab "RNA degradation" yog cov saum toj kawg nkaus cov ntsiab lus ntawm induced proteins. Cov txheej txheem kho DNA tau pom cov qauv qhia bipartite. Ntawm no, cov proteins uas koom nrog hauv kev txiav tawm nucleotide lossis kho qhov tsis sib haum tau raug tsim txom, tab sis cov kev sib kho "Base excision repair" raug ntxias. Tsis tas li ntawd, qib kev nplua nuj ntawm lub voj voog ntawm tes inhibitor p27Kip1 tau nce ob npaug (Daim duab 3C) thiab cov cim ntawm kev loj hlob Ki67 yog 3.4-fold txo (Daim duab 3D), uas ua ke qhia tias lub cell poob qis. txheej txheem faib. Tshwj xeeb, mRNA qhia theem ntawm Mki67, gene encoding rau Ki67, tau ua rau muaj kev cuam tshuam loj heev hauv nas thawj cov kab mob hauv cov kab mob hauv cov kab mob hauv cov kab mob hypoxic (Fig. 3E). Qhov kev tsim txom no tau kho los ntawm hypermethylation ntawm Mki67 txhawb nqa cheeb tsam hauv hypoxic fetal ob lub raum (Fig. 3F). Yog li, nyob rau hauv fetal hypoxic ob lub raum, DNA synthesis, mRNA translation, thiab feem ntau DNA kho txheej txheem zoo li yuav tsum tau muab tso tseg, txo lub peev xwm ntawm lub hlwb kom loj hlob thiab proliferate. Hauv kev sib sau ua ke ntawm no, thawj zaug, cov ntaub ntawv proteome profiling muab cov pov thawj molecular uas muaj peev xwm piav qhia txog qhov txo qis ntawm nephrons.
Lub Innate Immune System thiab Oxidative Stress tau qhib rau hauv cov mob Hypoxic ntev
Ib qho ntawm cov ntsiab lus muaj txiaj ntsig zoo tshaj plaws tshwm sim nyob rau hauv kev soj ntsuam kev ua haujlwm ntawm tag nrho 436 cov proteins thiab qhov siab tshaj plaws rau cov proteins uas raug ntxias yog "Neutrophil degranulation" (Fig. 2, B thiab C), qhia txog kev ua kom tsis tu ncua ntawm lub cev tsis muaj zog hauv lub cev.hypoxic fetal ob lub raum. Ntawm 34 cov proteins uas txuam nrog, 29 tau raug ntxias thiab tsib raug cem (liab liab hauv daim duab 4A). Ntawm cov induced proteins muaj ntau glycolytic thiab lysosome-txog enzymes, ob peb S100A protein cov neeg hauv tsev neeg, inflammatory cytokine macrophage migration inhibitory factor (MIF), nrog rau cov thawj thiab theem nrab granule proteins neutrophilic granule protein (NGP), myeloperoxidase (MPO) , Catelicidin (CAMP), peptidoglycan recognition protein 1 (PGLYRP1), thiab lactoferrin (LTF). Txhawm rau txheeb xyuas qhov kev cia siab ntawm kev cuam tshuam ntawm neutrophils hauv hypoxic fetal ob lub raum thiab txhawm rau nthuav tawm lawv qhov chaw nyob hauv cov ntaub so ntswg, lub raum seem tau stained rau MPO. MPO-zoo hlwb tsim pawg nyob rau hauv nephrogenic cheeb tsam ntawm lub raum cortex, nyob rau hauv qhov sib thooj ntawm cov hlab ntsha, nyob ib sab mus rau lub proximal tubule, thiab tej zaum yuav pom nyob rau hauv medullary cheeb tsam ntawm hypoxic kuaj (Fig. 4D thiab ntxiv Fig. S3, A. -C). Nyob rau hauv sib piv, normoxic fetal ob lub raum tsis qhia infiltration los yog tsub zuj zuj ntawm neutrophils (Fig. 4C). Caveolin-1 (CAV1) tau pom tias yuav txhim khu cov transcellular migration ntawm lub cev tiv thaiv kab mob (33). Raws li, CAV1 raug ntxias nyob rau hauv hypoxic fetal ob lub raum (supplemental Fig. S3D), uas qhia txog kev txhim kho staining ntawm lub raum cov hlab ntsha nrog rau cov traversing cheeb tsam cortical ntawm lub raum fetal (Fig. 4, E thiab F). Degranulation ntawm neutrophils ua rau lub zos tawg ntawm reactive oxygen hom ua rau muaj zog oxidative kev nyuaj siab thiab cov ntaub so ntswg puas xws li DNA oxidation. Ib qho tseem ceeb ntawm DNA oxidation yog 8-hydroxy-2' -deoxyguanosine (8-OHdG), uas tau txhim kho hauv cov tubules ze ze thiab hauv thaj tsam nephrogenic ntawm hypoxic fetal ob lub raum (Fig. 4, G thiab H), nyob ib puag ncig ntawm neutrophil pawg. Qhov no nce hauv 8-OHdG puas DNA tshwm sim txawm tias ib txhij induction ntawm MGMT thiab OGG1 (Fig. 4, I thiab J), ob enzymes lub luag hauj lwm rau kev tshem tawm ntawm 8-OHdG. Cov txiaj ntsig no qhia tau tias muaj kev ua kom tsis tu ncua ntawm lub cev tiv thaiv kab mob hauv lub raum, uas ua rau muaj kev puas tsuaj ntau ntxiv ntawm cov ntaub so ntswg ntxiv nrog rau kev ntxhov siab hypoxic. Nrog rau kev kho tsis zoo ntawm cov ntaub so ntswg, lub voj voog vicious tej zaum yuav pib uas ua rau nephrogenesis ntxiv.
FIG. 2. Proteomic profileing qhia ntau yam kev hloov pauv cuam tshuam nrog hypoxia. A, qhov tseem ceeb ntawm kev tsom xam ntawm cov ntaub ntawv proteomic pom qhov sib cais meej ntawm normoxic thiab hypoxic fetal ob lub raum. B-D, cov lus piav qhia ua haujlwm ntawm tag nrho cov proteins uas tsis zoo (B), cov proteins uas tau tsim (C), thiab txo cov proteins (D) Cov feem ntau hloov pauv ntawm txoj hauv kev (x-axis) yog npaj tawm tsam nws qhov tseem ceeb ntawm kev txhawb nqa (y- axis). Qhov loj ntawm txhua lub ntsiab lus encodes tag nrho cov tswv cuab hauv txoj kev ntawd. Induced proteins pom kev txhawb nqa ntawm cov txheej txheem metabolic (glycolysis), mitochondrial lossis lysosomal proteins, thiab cov proteins koom nrog hauv lub cev tiv thaiv kab mob (neutrophil degranulation), thaum txo cov proteins yog enriched rau DNA- thiab RNA-binding txoj kev (ib tug qauv ntawm ribosome).
(PGLYRP1), thiab lactoferrin (LTF). Txhawm rau txheeb xyuas qhov kev cia siab ntawm kev cuam tshuam ntawm neutrophils hauv hypoxic fetal ob lub raum thiab txhawm rau nthuav tawm lawv qhov chaw nyob hauv cov ntaub so ntswg, lub raum seem tau stained rau MPO. MPO-zoo hlwb tsim pawg nyob rau hauv nephrogenic cheeb tsam ntawm lub raum cortex, nyob rau hauv qhov sib thooj ntawm cov hlab ntsha, nyob ib sab mus rau lub proximal tubule, thiab tej zaum yuav pom nyob rau hauv medullary cheeb tsam ntawm hypoxic kuaj (Fig. 4D thiab ntxiv Fig. S3, A. -C). Nyob rau hauv sib piv, normoxic fetal ob lub raum tsis qhia infiltration los yog tsub zuj zuj ntawm neutrophils (Fig. 4C). Caveolin-1 (CAV1) tau pom tias yuav txhim khu cov transcellular migration ntawm lub cev tiv thaiv kab mob (33). Raws li, CAV1 raug ntxias nyob rau hauv hypoxic fetal ob lub raum (supplemental Fig. S3D), uas qhia txog kev txhim kho staining ntawm lub raum cov hlab ntsha nrog rau cov traversing cheeb tsam cortical ntawm lub raum fetal (Fig. 4, E thiab F). Degranulation ntawm neutrophils ua rau lub zos tawg ntawm reactive oxygen hom ua rau muaj zog oxidative kev nyuaj siab thiab cov ntaub so ntswg puas xws li DNA oxidation. Ib qho cim tseem ceeb ntawm DNA oxidation yog 8-hydroxy-2' -deoxyguanosine (8-OHdG), uas tau txhim kho nyob rau hauv cov tubules proximal thiab hauv thaj tsam nephrogenic ntawm hypoxic fetal ob lub raum (Fig. 4, G thiab H), nyob ib puag ncig ntawm neutrophil pawg. Qhov no nce hauv 8-OHdG puas DNA tshwm sim txawm tias ib txhij induction ntawm MGMT thiab OGG1 (Fig. 4, I thiab J), ob enzymes lub luag hauj lwm rau kev tshem tawm ntawm 8-OHdG. Cov txiaj ntsig no qhia tau tias muaj kev ua kom tsis tu ncua ntawm lub cev tiv thaiv kab mob hauv lub raum, uas ua rau muaj kev puas tsuaj ntau ntxiv ntawm cov ntaub so ntswg ntxiv nrog rau kev ntxhov siab hypoxic. Nrog rau kev kho tsis zoo ntawm cov ntaub so ntswg, lub voj voog vicious tej zaum yuav pib uas ua rau nephrogenesis ntxiv.
Metabolic Adaptations rau Hypoxia tshwm sim hauv Pronounced Glycolysis hauv Fetal raum
Mob hypoxia yog ib qho mob hnyav uas cov hlwb yuav tsum tau hloov kho los ntawm kev hloov pauv hauv metabolic thiaj li muaj sia nyob. Qhov tseem ceeb tshaj plaws rau qhov no yog kev saib xyuas ntawm cellular ATP ntau lawm uas thaum tsis muaj oxygenation txaus yuav tsum tau hloov ntawm oxidative phosphorylation mus rau glycolysis. Ntawm tag nrho cov ntsiab lus uas tshwm sim los ntawm kev ua haujlwm annotation, "glycolytic txheej txheem" yog qhov tseem ceeb tshaj plaws (Fig. 2B). Tag nrho kaum enzymes (liab ①–⑩ hauv daim duab 5A) xav tau rau kev hloov pauv cov piam thaj rau pyruvate tau raug ntxias hauvfetal hypoxic lub raumpiv nrog rau cov tswj normoxic (ib daim ntawv qhia txog cua sov yog qhia hauv daim duab 5C). Tsis tas li ntawd, cov kab lus ntawm glucose transporter 1 (SLC2A1, txiv kab ntxwv hauv daim duab 4A) thiab lactate dehydrogenase A (LDHA, tsaus liab hauv daim duab 5A) kuj tau txhim kho, uas yuav tsum ua kom muaj kev nce qib ntawm cov piam thaj mus rau hauv lub xovtooj ntawm tes thiab kev txo qis ntawm augmented. pyruvate rau lactate, feem. Lwm txoj kev siv pyruvate hauv lub voj voog citric acid zoo li raug cuam tshuam (1) los ntawm kev nthuav qhia ntawm pyruvate dehydrogenase kinase 1 (PDK1, tsaus liab hauv daim duab 5A), uas inactivates pyruvate dehydrogenase complex hauv mitochondria thiab yog li cov oxidation ntawm pyruvate. rau acetyl-CoA; thiab (2) los ntawm kev txo qis ntawm pyruvate carboxylase (PC), uas catalyzes hloov pauv ntawm pyruvate rau oxaloacetate. Ntawm qhov tod tes, fructose-1,6-bisphosphatase 1 (FBP1, xiav hauv daim duab 5A) raug txo qis, ntxiv rau qhov muaj peev xwm flux ntawm qabzib mus rau pyruvate. Tag nrho cov kev hloov enzymatic no txaus siab rau kev tsim cov lactate, thiab qhov tseeb, lactate concentration tau nce hauv hypoxic fetal ob lub raum (Fig. 5B). Txhim kho lactate ntau lawm tuaj yeem ua rau tsis zoo acidification. Txawm li cas los xij, peb pom ntawm cov proteins uas muaj nplua nuj nyob hauv monocarboxylate transporters SLC16A3 thiab SLC5A8 (txiv kab ntxwv hauv daim duab 5A), uas paub tias yuav tso lactate rau hauv qhov chaw ntxiv kom tsis txhob muaj tshuaj lom ntawm cytoplasmic acidification. Yog li, peb tus qauv qhia tau hais tias muaj peev xwm zoo tshaj plaws ntawm lub raum hauv plab kom hloov mus rau qhov mob hypoxia los ntawm kev ua kom glycolytic,
FIG. 3. Kev tsim ntawm cov nephrons tshiab hauv hypoxia yog txuam nrog repressed DNA replication thiab protein synthesis. A, protein sib cuam tshuam network ntawm kev hloov pauv DNA- thiab RNA-binding proteins tau los ntawm STRING database qhia ntau pawg protein: ribosomal proteins (xiav), proteins koom nrog DNA replication (ntsuab), DNA kho (ntsuab), thiab mRNA splicing ( liab). Cov cim kev loj hlob Ki67 (Mki67) yog cim dub, qhia txog nws txoj kev sib raug zoo rau DNA kho thiab rov ua dua DNA. B, ib qho kev xaiv ntawm txoj hauv kev hloov pauv DNA- thiab RNA-binding proteins los ntawm KEGG thiab Reactome databases uas nthuav tawm qhov kev hloov pauv tseem ceeb tshaj plaws hauvhypoxic lub raum, depicted nyob rau hauv txo qhov kev txiav txim ntawm qhov tseem ceeb. RNA splicing thiab RNA degradation txheej txheem tau enriched (liab), thaum RNA translation, DNA replication, thiab kho txoj kev raug repressed (xiav). Tsuas yog cov txheej txheem nrog FDR<0.05 are shown. C and D, the cell cycle inhibitor p27Kip1 was enhanced (unpaired two-tailed t test, Welch's correction, p = 0.0095), whereas the expression of the proliferation marker Ki67 was reduced (unpaired two-tailed t test, Welch's correction, p = 0.0078) in hypoxic fetal kidneys. E, hypoxia reduced the mRNA expression level of Mki67 in mouse primary proximal tubular cells (unpaired two-tailed t test, p < 0.0001). F, this reduction was mediated by hypermethylation of the Mki67 promoter in hypoxic fetal kidneys. Open circle unmethylated, black circle methylated (Fisher's exact test, p = 0.0016; Mann–Whitney U-test, p = 0.0431)
FIG. 4. Proteins koom nrog inflammatory teb thiab oxidative kev nyuaj siab yog enriched nyob rau hauv tshiab tsim nephrons nyob rau hauv hypoxia. A, kev piav qhia ntawm tag nrho 34 cov protein hloov pauv loj rau cov lus piav qhia hu ua neutrophil degranulation (paj liab lub voj voog) ntawm txhua qhov tseem ceeb (cov voj voog grey loj) thiab tsis tseem ceeb (me me grey voj voog) cov proteins ntawm peb cov ntaub ntawv teev. 29 muaj ib tug ntau dua abundance, whereas tsib raug txo. B, daim ntawv qhia ua kom sov uas qhia tag nrho cov proteins liab hauv (A) thiab lawv qhov kev cuam tshuam lossis kev tsim txom hauv hypoxia, qhia txog kev txo qis ntawm cov protein ntau. C-H, tus neeg sawv cev immunohistochemical cov duab ntawm E18.5 normoxic lossishypoxic lub raumqhia cov infiltration ntawm neutrophils thiab oxidative kev nyuaj siab. C thiab D, immunohistochemistry rau cov neutrophil marker myeloperoxidase (MPO) qhia txog kev sib koom ua ke ntawm cov hlwb hauv qhov sib thooj ntawm cov nephrons tshiab (asterisk) thiab nyob ib sab ntawm lub raum cov hlab ntsha (xws taub hau) ntawm hypoxic fetal ob lub raum (D). Hauv kev tswj hwm normoxic (C), MPO-zoo hlwb tsis tshua muaj. (Sale bars 100 μm). E thiab F, immunohistochemistry depicting enhanced expression of caveolin-1 (CAV1) nyob rau hauv lub raum cov hlab ntsha ntawm hypoxic fetal ob lub raum (F) piv nrog cov tswj (E) (Scale bars 200 μm). G thiab H, 8-hydroxy-2′ -deoxyguanosine (8-OHdG), ib qho cim rau oxidative DNA puas, tau ua kom zoo dua qub hauv cov nephrons tshiab (asterisk) hauv lub raum cortex thiab hauv cov hlwb ntawm cov tubules ze ze ( xub) ntawm lub raum hypoxic (H), tab sis tsuas yog ob peb lub hlwb tau stained hauv cov ntaub so ntswg (G) (Scale bars 200 μm). Kuv thiab J, qhov kev nce hauv DNA puas tau tshwm sim txawm tias muaj kev nce ntxiv hauv O-6-methylguanine-DNA methyltransferase (MGMT; unpaired two-tailed t test, p=0.0002) (I) thiab {{ 15}}oxo guanine glycosylase (OGG1; unpaired two-tailed t-test, p=0.0063) (J), ob lub enzymes koom nrog kho cov oxidized DNA.
uas ua kom txaus ATP ntau lawm thiab muaj sia nyob raws li qhov tsis zoo no.
Fetal Hypoxia txhawb nqa Compensatory MitochondrialProtein ntshuam thiab ua pa Chain Assembly
Dhau li ntawm kev txhim kho glycolysis, peb pom muaj ntau yam kev hloov pauv hauv mitochondrial protein ntau ntau ntau (ib daim ntawv qhia ua cua sov tau qhia hauv cov duab ntxiv S4). Kev tsim cov kev sib txuas ntawm cov protein siv STRING tau nthuav tawm ntau pawg uas muaj cov proteins uas koom nrog kev hloov pauv cov proteins mus rau hauv mitochon.dria, oxidative phosphorylation, thiab mitochondrial ribosomal proteins (Fig. 5, D thiab E). Ntawm qhov kev ceeb toom, ntau cov proteins uas txuas nrog rau sab hauv mitochondrial membrane raug ntxias, qhov chaw uas oxidative phosphorylation (OXPHOS) tshwm sim. Ntawm cov induced proteins yog cov Cheebtsam ntawm OXPHOScomplexes (NDUSF6), III (UQCR10), IV (COX6B1, COXC, thiab COX7A2), thiab V (ATP5J, MTATP8), tab sis kuj UQCC3 thiab SCO2, uas yog yuav tsum tau rau kev sib dhos thiab ua haujlwm kom raug. ntawm complex thiab IV, raws li (Fig. 5D thiab ntxiv Fig. S4). SDHC thiab SDHD, subunits ntawm complex ll, kuj tau upregu.lated (1.6- thiab 2.5-fold, ntsig txog), tab sis tsis ncav cuag qhov tseem ceeb. Tsis tas li ntawd, tsis tsuas yog cov khoom ntawm cov kab mob ua pa tau ntxiv rau hauv fetalhypoxic lub raum, tab sis kuj muaj ntau ntawm cov proteins kho lawv cov ntshuam mus rau mitochondria. Qhov no suav nrog cov tswvcuab ntawm cov txheej txheem sab nrauv (TOM - TOMM22), thiab sab hauv daim nyias nyias translocase complex TIM22 (TIMM22, TIMM9, thiab TIMM10 thiab cov koom nrog TIMM8-TIMM13-} complex (Fig. 5D thiab ntxiv Fig. . S4). Ntawm 21 mitochondrial proteins uas txo abundance yog plaub mitochondrial ribosomal proteins, nrog rau cov proteins koom nrog amino acid catabolism, vitamin biosynthesis, los yog fatty acid beta-oxidation (Fig. 5, D thiab E, thiab ntxiv Fig. S4). Cov kev tshawb pom no taw qhia rau pawg ntseeg muaj peev xwm mitochondrial tsis ua haujlwm thiab pom meej rau kev tsim cov proteins uas puas lawm (34), txawm tias txhim kho glycolysis thiab tag nrho txo cov protein synthesis.
Lysosomal Biogenesis thiab Autophagy tau txhim kho hauvHypoxic Fetal raumLub lysosome yog tus thib ob organelle uas zoo li yuav enriched nyob rau hauv hypoxic mob. Txawm li cas los xij, nyob rau hauv kev sib piv rau mitochondria, qhov twg 36% ntawm cov proteins raug txo, yuav luag tag nrho cov lysosome-related proteins tau upregulated (Fig. 6, A thiab B). Ntawm lawv yog cuaj lysosomal acid hydrolases, sawv cev ze li ntawm 20% ntawm lysosomal acid hydrolases sau tseg hauv KEGG txoj hauv kev rau lysosomes: plaub pro teases (CTSA, CTSF, CTSZ, TPP1), peb glycosidases (GAA, NAGA, NEU1), lysosomal. acid phosphatase 2 (ACP2), thiab lysosomal acid lipase A (LIPA). Tsis tas li ntawd, peb pom cov pov thawj rau kev nce biogenesis ntawm lysosomes thiab lwm yam organelles. Peb ntawm yim BLOC1 (biogenesis ntawm lysosome-related organelles complex 1) Cheebtsam tau induced ho (Fig. 6, C–E), as well as H/Cl exchange transporter 5 (CLCN5), uas yog ib tug tseem ceeb players nyob rau hauv lub acidification ntawm endosomes (Fig. 6F). Ntawm qhov kev ceeb toom, Snapin (BLOC1 subunit 7) kuj ua lub luag haujlwm hauv lysosomal acidification thiab hauv autophagosome maturation thiab muaj nuj nqi. Lwm yam induced proteins paub ua lub luag hauj lwm nyob rau hauv autophagy yog Atg7 thiab Bnip3 (Fig. 6, G thiab H). Lwm qhov yuav tsum tau ua rau autophagic flux yog qhov perinuclear clustering ntawm lysosomes, kho los ntawm lysosomal Ragulator complex (35, 36) thiab ob tsev neeg tawm tsam lub cev muaj zog. Strikingly, plaub ntawm tsib tus tswv cuab ntawm Regulator scaffolding subunits (LAMTOR1, 2, 3, thiab 5) tau raug cuam tshuam loj heev (Fig. 6, A thiab B); LAMTOR4 kuj yog 1.81-fold induced, tab sis tsis ncav cuag qhov tseem ceeb. Tsis tas li ntawd, kinesins, uas kho kom haum rau sab nraud ntawm cov organelles, tau pom tias muaj kev cuam tshuam rau kev tsim txom, thaum dynein cov neeg hauv tsev neeg uas pab txhawb kev txav sab hauv raug ntxias, txawm hais tias tsis yog qhov tseem ceeb (supplemental Fig. S5). Sib sau ua ke cov kev tshawb pom no muab pov thawj muaj zog tias kev ua haujlwm hauv tsev ntawm lysosomes tau txhim kho hauvfetal hypoxic lub raum, tag nrho sib xws nrog qhov xav tias yuav tsum tau rov ua dua mitochondria puas.
ntxov ntxov
Kev laus ua piv txwv Janus-Faced Aspects of Hypoxic Adaptation Opposatory to the compensatory kho thiab rejuvenation mechanisms, peb pom 15 ntawm cov deregulated proteins uas yog GO lub sij hawm "Aging" (Fig. 7A), sawv cev rau thib peb qeb ntawm hypoxic adaptations: accelerated aging. . Thaum feem ntau ntawm cov proteins no ua lub luag haujlwm hauv ib qho ntawm cov txheej txheem tau piav qhia saum toj no neutrophil degranulation thiab lyso somes (MIF, MPO, PSEN1), mitochondria (NDUFS6, FADS1, MTCO1, CYP27B1), glycolysis (ALDOC), thiab kho DNA (OGG1) ; qee qhov tau piav qhia ncaj qha rau lub neej ntev ntawm nas. Hauv particular, cov protein ntau ntawm ob qho tib si klotho thiab sirtuin 6 tau txo qis hauv E18.5 hypoxic.lub raum fetal(Daim duab 7, B thiab C). Sirtuin 6 yog ib qho enzyme uas tau nthuav tawm thoob plaws nrog cov protein deacetylase thiab mono-ADP ribosyl transferase kev ua haujlwm koom nrog hauv kev tswj hwm ntawm ntau lub xov tooj ntawm tes, suav nrog kev mob, glycolysis, thiab kho DNA. Nws knockout ua rau muaj mob loj heev hauv cov nas nrog lub neej luv ntawm 1 txog 3 lub hlis (37, 38). Lub raum yog qhov chaw loj ntawm klotho synthesis (piv txwv li, distal convoluted tubule-DCT txhawb nqa feem ntau ntawm cov protein nrog ntxiv synthesis nyob rau hauv lub proximal convoluted tubules), qhov uas nws ua nyob rau hauv zos raws li ib tug membrane-bound beta-glucuronidase. Qhov txo qis ntawm klotho zoo li yog cov txheej txheem tshwj xeeb vim tias lwm cov proteins ntawm DCT suav nrog CALB1 tsis tau hloov pauv. Klotho kuj tseem zais cia rau hauv txoj kev ncig los ntawm kev sib cais ntawm cov khoom siv sab nraud ntawm daim nyias nyias los yog los ntawm kev txhais lus ntawm lwm qhov sib txawv. Cov theem ntawm klotho (sKL) txo qis thaum muaj hnub nyoog (39, 40), uas ua rau peb ntsuas nws cov concentration thiab cov sirtuin 6 hauv lub cev ntawm hypoxic lossis normoxic E18.5 fetuses. Tseeb, qhov concentrations ntawm sKL thiab sirtuin 6 tau txo qis hauv hypoxic E18.5 fetuses (Fig. 7, D thiab E). Tsis tas li ntawd thiab qhov tseem ceeb, cov qib ntshav ntawm klotho thiab sirtuin 6 kuj tseem txo qis hauv cov nas muaj hnub nyoog (Fig. 7, F thiab G), qhia tias yuav txo qis ntawm ob cov proteins no mus tas li. Rau Klotho, qhov no zoo li yog vim qhov txo qis ntawm mRNA qhia ntau ntau hauv ob lub raum ntawm 15-hli cov xeeb ntxwv hypoxic (Fig. 7H). Txawm li cas los xij, lub raum mRNA qhia theem ntawm sirtuin 6 tsis hloov pauv ntawm cov nas muaj hnub nyoog normoxic thiab hypoxic (Fig. 7I). Tsis tas li ntawd, kev hloov pauv hauv DNA methylation tau pom tias yog ib qho ntawm cov txheej txheem tseem ceeb tshaj plaws tsis yog rau nephron progenitor cell txuas ntxiv thiab sib txawv (41), tab sis kuj rau klotho qhia (42, 43). Txawm li cas los xij, nyob rau hauv sib piv rau hypermethylation ntawm Mki67 (Fig. 3F), klotho txhawb nqa tau hypomethylated thaum lub sij hawm mob hypoxia (supplemental Fig. S6). Tus qauv methylation ntawm Sirt6 tsis tuaj yeem txiav txim siab. Rau qhov zoo tshaj plaws ntawm peb txoj kev paub, peb tus qauv IUGR yog thawj zaug los piav qhia txog lub tswv yim ua rau muaj kev laus ntxov ntxov phenotype, los ntawm kev sib koom ua ke ntawm kev puas tsuaj, kev kho tsis zoo, hloov pauv cov metabolism, thiab txo qis cov protein ntau ntawm cov tshuaj tiv thaiv thaum yug los.
Qhov txo qis ntawm Antiaging Proteins nyob rau hauv Teb rau Chronic Hypoxia yog Conserved ntawm nas thiab txiv neej Nyob rau hauv ib tug xeem txheej ntawm thwmsim, peb nug seb qhov interplay ntawm mob hypoxia thiab txo cov ntshav cov ntshav ntawm antiaging proteins yog ib tug evolutionarily conserved tshwm sim. Txog rau qhov kawg no, cov qauv kuaj ntshav los ntawm kev tswj xyuas (10) ntawm cuaj tus neeg ua haujlwm noj qab haus huv (yim tus txiv neej, ib tus poj niam) tau sau 2 lub lis piam ua ntej (sea level, SL), ntawm peb-lub sij hawm cov ntsiab lus thaum lub sij hawm tsis muaj kev cuam tshuam 28-hnub sojourn ntawm 3454 m (high altitude, HA3, HA9, HA28), thiab 1, 7, thiab 14 hnub tom qab lawv rov qab mus rau SL (RSL1, RSL7, RSL14) tau soj ntsuam rau sKL thiab SIRT6 (Fig. 8). Cov qauv uas tau txais ntawm SL tau txais kev tswj hwm rau txhua tus neeg koom. sKL thiab SIRT6 cov ntshav ntshav poob qis ntawm qhov siab siab thiab ob qho tib si tau mus txog qhov muaj feem cuam tshuam ntawm H28. Thaum rov qab mus rau qib dej hiav txwv, sKL tau nce mus rau qib siab dua ua ntej nyob ntawm qhov siab ntawm RSL7 thiab rov qab mus rau qhov qub ntawm RSL14 (Fig. 8A). Ntawm qhov tod tes, SIRT6 txuas ntxiv poob qis thaum rov qab mus rau qib dej hiav txwv thiab tsuas yog pib incline dua ntawm RSL14 (Fig. 8B), qhia txog kev sib txawv ntawm ob txoj kev tiv thaiv kev laus. Hauv cov ntsiab lus, cov kev tshawb pom no qhia tias txo cov ntshav klotho thiab sirtuin 6 qib feem ntau yuav tsum tau raug rau cov mob hypoxic ntev thiab tuaj yeem sawv cev rau cov txheej txheem evolutionary heev txuag.
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