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Kev paub

Yuav kho thiab kho mob raum mob li cas?

Mar 14, 2022

Hu rau: Audrey Huaudrey.hu@wecistanche.com

Multi-omic mus kom ze rau mob raum raug mob thiab kho

Louisa MS Gerhardt thiab Andrew P. McMahon

Abstract

Lub raum muaj peev xwm regenerative zoo kawg li. Nyob rau hauv teb rau ischemic los yog tshuaj lom raug mob, proximal tubule hlwb tuaj yeem proliferate los tsim cov tubules puas thiab rov ua haujlwm rau lub raum. Txawm li cas los xij, hnyav heevmob raum raug mob(AKI) lossis rov tshwm sim AKI (mob raum raug mob) cov xwm txheej tuaj yeem ua rau kev kho mob tsis zoo thiab kev kis kab mob los ntawm AKI (mob raum raug mob) raumob raum mob(CKD). Daim ntawv thov ntawm cov thev naus laus zis ib leeg tau txheeb xyuas qhov raug mob ntawm cov tubule cell xeev lub lis piam tom qab AKl (mob raum raug mob), distinguished los ntawm ib tug proinflammatory senescent molecular kos npe. Cov kev tshawb fawb Epigenetic tau qhia txog kev hloov pauv hloov pauv hauv thaj chaw chromatin ntawm lub raum tom qab AKI (mob raum raug mob)thiab tau piav qhia txog cov ntsiab lus tseem ceeb txuas rau AKI (mob raum raug mob) teb. Kev sib koom ua ke ntawm ntau lub tshuab thev naus laus zis qhib qhov muaj peev xwm tshiab los txhim kho peb txoj kev nkag siab ntawm AKI (mob raum raug mob) thiab cov tsav tsheb tom qab AKl (mob raum raug mob)-rau-CKD kev hloov pauv, nrog rau lub hom phiaj kawg ntawm kev tsim kho kom haum rau kev kuaj mob thiab cov tswv yim kho mob los txhim kho AKI (mob raum raug mob) qhov tshwm sim thiab tiv thaivmob raumkev vam meej.

Ntsiab lus: Mob raum raug mob, Multi-omics, Epigenomics, ib leeg-cell RNA-sequencing, ATAC sequencing.

BENEFIT OF CISTANCHE

Taw qhia

Mob raum raug mob(AKI), kuaj pom los ntawm kev nce sai ntawm cov ntshav creatinine thiab / lossis txo qis ntawm cov zis ntim, yog ib qho mob hnyav heev uas cuam tshuam nrog kev mob hnyav ntxiv thiab kev tuag nrog rau cov nqi kho mob tseem ceeb [1e4]. Piv txwv li, cov pov thawj tam sim no qhia tias tsawg kawg 25 feem pua ​​​​ntawm tag nrho cov neeg mob hauv tsev kho mob COVID-19 tsim AKI (mob raum raug mob) thiab tias cov neeg mob no muaj kev pheej hmoo tuag ntau dua li COVID-19 cov neeg mob uas tsis muaj AKI (mob raum raug mob) [5]. Cov neeg mob muaj sia nyob AKI (mob raum raug mob) muaj kev pheej hmoo ntawm kev hloov mus rau mob raum thiab mob raum kawg [3,4,6]. Raws li 2018 US Renal Data System daim ntawv tshaj tawm txhua xyoo, tsuas yog 52.6 feem pua ​​​​ntawm cov neeg mob hauv tsev kho mob Veteran Affairs, uas tau ntsib AKI. (mob raum raug mob)Cov txheej txheem kuaj mob, tau muab kev kuaj mob AKI (mob raum raug mob), hu kom paub ntau ntxiv rau AKI (mob raum raug mob) hauv tsev kho mob niaj hnub [7]. Tsis tas li ntawd, kev kuaj mob ntxov ntawm AKI (mob raum raug mob)raug txwv los ntawm qhov tsis muaj biomarkers rhiab heev, thiab muaj kev kho mob rau AKI (mob raum raug mob) txuas ntxiv tso siab rau hemodynamic optimization, zam ntawm nephrotoxicity, thiab kho lub raum hloov.

Proximal tubule cells, hom cell uas muaj ntau tshaj plaws hauv lub raum, yog lub luag haujlwm rau ib feem ntawm lub raum kua dej thiab cov kua dej reabsorption thiab tau tshwm sim los ua cov players loj hauv kev hloov pauv thiab cov lus teb tsis zoo rau AKI (mob raum raug mob) [8]. Vim tias lawv cov kev ua haujlwm metabolic siab thiab kev vam khom rau oxidative metabolism, ischemia sai ua rau ATP depletion, tsub zuj zuj ntawm cov pa oxygen reactive, thiab thaum kawg apoptosis lossis necrosis ntawm proximal tubule cells (Daim duab 1). Proximal tubule hlwb uas ciaj sia ib qho kev tshwm sim ischemic muaj peev xwm mus dedifferentiate, proliferate, thiab rebuild puas tubules, yog li ua si ib qho tseem ceeb nyob rau hauv cov txheej txheem kho kho kom rov qab ua haujlwm rau lub raum [9-11]. Txawm li cas los xij, maladaptive proximal tubule hlwb, tus cwj pwm los ntawm cov kab mob proinflammatory thiab profibrotic phenotype, kuj tau cuam tshuam rau kev kis kab mob los ntawm AKI (mob raum raug mob) rau cov kab mob raum ntev (CKD), cov txheej txheem nyuaj uas cuam tshuam nrog o, vascular rarefaction, thiab extracellular matrix ntau lawm los ntawm activated pericytes thiab myofibroblasts (Daim duab 1) [8,12]. Omics thev naus laus zis tshuaj xyuas lub koom haum genomic, gene qhia, thiab cov khoom lag luam protein, xws li kev soj ntsuam rau transposase-accessible chromatin siv sequencing (ATAC-seq), mRNA sequencing, thiab huab hwm coj spectrometry, raws li, tau ua kom zoo dua molecular kev pom rau hauv cellular teb pib los ntawm AKI (mob raum raug mob). Tsis ntev los no, ib leeg-cell daim ntawv thov ntawm cov txheej txheem no tau ua rau txoj kev tshawb fawb ntawm cov xwm txheej ntawm tes ntawm kev daws teeb meem tsis tau pom dua. Cov no thiab lwm yam kev ua ntau yam omics tuav cov lus cog tseg ntawm kev nkag siab zoo ntawm cov txheej txheem tswj hwm kev tswj hwm kab mob raum, qhib txoj hauv kev tshiab rau biomarker thiab tshawb nrhiav tshuaj. Cov ntawv sau no tshuaj xyuas cov kev tshawb pom tsis ntev los no siv omics thev naus laus zis raumob raumthiab kho thiab txiav txim siab yav tom ntej daim ntawv thov ntawm ntau txoj hauv kev omic kom nkag siab thiab kho ntawmmob raumthiabmob raum.

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Daim duab 1:Txheej txheem cej luam ntawm AKI thiab cov txheej txheem.

Proximal tubule cells muaj kev cuam tshuam rau ischemia, uas tuaj yeem ua rau tuag ntawm tes los ntawm apoptosis thiab tswj tau (pyroptosis, ferroptosis, necroptosis) nrog rau qhov tsis raug cai necrosis thiab sloughing ntawm ob lub hlwb tuag thiab siv tau rau hauv tubular lumen. Ciaj sia nyob ze ntawm tubule hlwb (PTCs) tuaj yeem ua rau muaj kev cuam tshuam thiab loj hlob los kho lub raum architecture thiab kev ua haujlwm; Txawm li cas los xij, kev kho tsis zoo kuj tuaj yeem ua rau muaj kab mob mus rau kab mob raum ntev (CKD). Cov txheej txheem no yog tus cwj pwm los ntawm vascular rarefication, pericyte rau myofibroblasts sib txawv, txhim kho fibrous extracellular matrix (ECM) deposition, tubular poob, thiab mob o. Nfkb1 ntxiv rau qhov ua tsis tiav-kho PTCs, tus cwj pwm los ntawm kev sib koom ua ke ntawm kev zais zais zais zais (SASP), yuav ua lub luag haujlwm tseem ceeb hauv AKI (mob raum raug mob)Převod CKD na TXK

BENEFIT OF CISTANCHE

Genomics

Cov kev tshawb fawb genomic tsom txhawm rau txheeb xyuas lub hauv paus caj ces ntawm tus kab mob los ntawm kev xav-tsav lub hom phiaj sib luag ntawm cov neeg sib tw cov noob los yog kev xav tsis muaj tag nrho-genome sequencing. Ntawm no, peb yuav tsom mus rau genome-wide Association cov kev tshawb fawb (GWAS) uas siv txoj hauv kev tsis sib haum xeeb los qhia cov kab ke sib txawv thoob plaws tag nrho cov genome rau phenotypic cov yam ntxwv xws li kab mob thiab tso cai rau tus neeg sib tw gene identification rau cov kev tshawb fawb mechanistic (Daim duab 2). Piv nrog rau lwm yam kab mob, tus naj npawb ntawm GWAS nug txog keeb kwm keeb kwm ntawm AKI (mob raum raug mob) yog tsawg. Qhov no yog ib feem ntawm qhov complex thiab heterogenic xwm ntawm AKI (mob raum raug mob) raws li tus kab mob. AKI (mob raum raug mob) tuaj yeem tshwm sim los ntawm ntau yam sib txawv xws li ischemia, sepsis, tshuaj nephrotoxic, thiab obstructive nephropathy. Cov pov thawj tam sim no qhia tau hais tias cov hauv paus molecular thiab cellular mechanisms ntawm AKI (mob raum raug mob) muaj cov laj thawj tshwj xeeb [13,14], tab sis qhov kev pom zoo txhais ntawm AKI (mob raum raug mob) - kev hloov hauv cov ntshav creatinine thiab cov zis tso zis - tsis suav nrog AKI sib txawv (mob raum raug mob) ua rau.

Ib qho kev ua haujlwm yooj yim rau kev kawm txog genome-wide koom haum (GWAS) yog qhia txog (sab laug sab laug). Txhawm rau kawm txog kev sib koom ua ke ntawm cov noob caj noob ces thiab ib qho tshwj xeeb, tag nrho-genome sequencing los yog genotyping siv ib leeg-nucleotide polymorphism (SNP) arrays yog ua rau cov pej xeem thiab cov kev txheeb xyuas kev sib raug zoo yog siv los txheeb xyuas SNPs cuam tshuam nrog kev txaus siab. Rau ib leeg-cell RNA sequencing (sab saum toj sab xis), ib leeg-cell ncua kev kawm ntawv yog npaj, ib leeg hlwb raug rho tawm thiab cov mRNA molecules ntawm lub cell (los yog nucleus) raug ntes ntawm hlaws dai rau tom ntej hloov mus rau cDNA. cDNA yog amplified thiab sequences txiav txim los ntawm lwm tiam neeg sequencing (NGS) thiab sequence mapping rau genome. Rau kev tsom xam epigenomic (hauv qab txoj cai), ib qho kev ntsuam xyuas rau transposase-accessible chromatin (ATAC) yog ua raws los ntawm NGS thiab cov kab ke ua ke kom pom cov genome-wide chromatin nkag tau. Hyperactive Tn5 transposase (Tn5) yog siv rau tshwj xeeb cleave qhov chaw ntawm qhib chromatin thiab ib txhij ntxig sequencing adapters rau NGS. Cov cheeb tsam ntawm cov chromatin nce ntxiv tau pom tias yog ATAC peaks. Rau kev tsom xam proteomics los ntawm huab hwm coj spectrometry (hauv qab sab laug), cov proteins raug muab rho tawm, zom rau hauv peptides, thiab ionized. Nyob rau hauv cov huab hwm coj spectrometer, ions yog ceev, raug rau ib tug magnetic teb, thiab lawv cov huab hwm coj-rau-them piv yog ntsuas, tso cai rau kev txheeb xyuas cov protein thiab kom muaj nuj nqis.

Txog niaj hnub no, ob lub GWAS loj dua tau nug txog keeb kwm keeb kwm ntawm AKI (mob raum raug mob). Thawj qhov kev tshawb fawb pom tau tias muaj kev koom tes ntawm ib leeg nuclear polymorphisms (SNPs) hauv GRM7 LMCD1-AS1 thiab BBS9 locus nrog coronary bypass graft phais-txog AKI (mob raum raug mob) nyob rau hauv ib qho kev tshawb pom ntawm 873 tus neeg mob thiab ib pawg neeg rov ua dua [15]. Qhov thib ob ua ke cov neeg mob los ntawm ob pawg sib txawv los tsim cov neeg tshawb pom ntawm 1429 cov neeg mob hnyav thiab txheeb xyuas plaub AKI (mob raum raug mob)-koom nrog SNPs nyob ze rau ntawm interferon regulatory factor 2 (IRF2) los yog transcription factor T-box 1 (TBX1) [16]. Interestingly, IRF2 tau txuas nrog pyroptosis thiab muaj lub luag haujlwm tswj hwm hauv lub cev tiv thaiv kab mob [17,18] thiab TBX1 yog ib feem ntawm T lub thawv noob tsev neeg, ib pawg ntawm cov txheej txheem hloov pauv nrog lub luag haujlwm tseem ceeb hauv txoj hmoo ntawm tes thiab kev tswj hwm lub xeev ntawm tes [19 ]. Txawm li cas los xij, kev koom tes ntawm AKI (mob raum raug mob) thiab cov loci no tsis tuaj yeem muab rov ua dua nyob rau hauv ib qho kev tshwm sim ntawm cov neeg mob hnyav, uas tau tshwj xeeb genotyped rau cov txheeb xyuas SNPs[20]. Qhov no qhia txog qhov tsim nyog ntawm cov qauv loj dua rau yav tom ntej AKI (mob raum raug mob) GWAS thiab qhia txog qhov nyuaj hauv kev txheeb xyuas cov caj ces muaj feem cuam tshuam rau cov kab mob heterogeneous xws li AKI (mob raum raug mob).

Tsis tas li ntawd, kev nthuav qhia ntau yam zoo loci (eQTL) kev tshuaj ntsuam xyuas yuav pab tau kev txhais lus ntawm kev nkag siab tau txais los ntawm GWAS rau cov txheej txheem kab mob. OTL kev tshuaj xyuas txhawm rau txheeb xyuas loci uas piav qhia ib feem ntawm cov noob qhia qhov txawv ntawm cov ntaub so ntswg thiab tuaj yeem siv los txuas SNPs hauv cov genome uas tsis yog coding rau lub hom phiaj gene qhia. Piv txwv li, ib qho kev sib koom ua ke ua ke nrog GWAS, eOTL, thiab kev sim ua haujlwm tau coj mus rau kev txheeb xyuas cov noob koom nrog hauv cov kab mob ntawm CKD [21-23].

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Daim duab 2:Schematic ntawm xaiv omics technologies.

Cov ntaub ntawv sau tseg

Kev tshwm sim ntawm cov thev naus laus zis tshiab uas tuaj yeem tshawb xyuas cov ntaub ntawv ntawm cov hlwb hauv lub raum raug mob tau hloov pauv peb txoj kev nkag siab ntawm cov lus teb ntawm tes rau AKI (mob raum raug mob), uncovering tshiab cell states thiab high-lighting dynamically hloov transcriptional toj roob hauv pes kho lub raum. Lub raum bulk mRNA sequencing nyob rau hauv ib xyoos tom qab AKI (mob raum raug mob) pom tau hais tias lub cev tshwj xeeb ntawm cov noob hloov pauv cuam tshuam txog kev raug mob tubular, kev loj hlob, kho, fibrosis, thiab kev tiv thaiv kab mob [24]. No nas AKI (mob raum raug mob) biobank cov ntaub ntawv qhia tau hais tias cov noob caj noob ces tseem raug kho dua ib xyoos tom qab AKI (mob raum raug mob), qhia txog qhov mob tsis tu ncua raws li qhov ua rau muaj tus kabmob kis mus rau CKD. Bulk mRNA sequencing ntawm niaj hnub hloov lub raum biopsies tso cai rau profiling ntawm luv luv- thiab ntev-ntev transcriptional hloov nyob rau hauv tib neeg lub raum transplants tshwm sim los ntawm lub ischemia / reperfusion raug mob (IRI) thaum lub sij hawm hloov pauv [25]. Txhua lub raum biopsies tau noj nyob rau hauv thawj teev tom qab reperfusion pom ib tug zoo xws li transcriptional profile cim los ntawm kev ua kom tam sim ntawd- mus rau thaum ntxov- teb cov noob, ntau yam uas encode transcriptional regulatory yam tseem ceeb.

Thaum 3 thiab 12 lub hlis tom qab hloov pauv, txawm li cas los xij, ob txoj hauv kev sib txawv uas cuam tshuam nrog kev rov qab los lossis kev loj hlob mus rau CKD tuaj yeem txiav txim siab. CKD-zoo li trajectory qhia downregulation nyob rau hauv cov kev qhia ntawm noob muaj feem xyuam rau mitochondrial biogenesis thiab upregulation ntawm o-thiab fibrosis-cuam tshuam cov noob, raws li pom nyob rau hauv tus nas qauv ntawm AKI (mob raum raug mob[24, 25] ib. Ob leeg nas thiab tib neeg cov kev tshawb fawb qhia txog lub luag haujlwm tseem ceeb rau T- thiab B-cell kev ua haujlwm thiab qhov pom ntawm cov chaw ntawm cov ntaub so ntswg tertiary lymphoid hauv cov txiaj ntsig ntev ntawm AKI (mob raum raug mob[25, 26] ib. Analysis ntawm nas AKI (mob raum raug mob) bio-bank thiab tib neeg lub raum hloov cov ntaub ntawv teeb tsa kev sib cav rau kev ua haujlwm ntawm nws tus kheej-antigen-tsav B-cell, txhawb kev kis kab mob los ntawm kev tiv thaiv kab mob, ib xyoos tom qab AKI (mob raum raug mob) [27].

Txawm hais tias feem ntau mRNA sequencing tau ua pov thawj tias muaj ntaub ntawv ntau hauv AKI (mob raum raug mob) kev tshawb fawb, cov lus teb ntawm tes-hom tshwj xeeb tsis txawv ntawm cov txheej txheem no. Cov txheej txheem caj ces rau kev sau cov npe sib txawv ntawm tes ntxiv qhov tseeb dua thiab kev pom ntxiv. Piv txwv li, txhais lus ribosome affinity purification (TRAP) siv ib qho eGFP tagging ntawm L10a ribosomal subunit los txheeb xyuas qhov tshwj xeeb mRNA subset nyob rau hauv ib lub xov tooj ntawm tes uas tau txais kev txhais lus [28]. Thawj txoj kev kawm TRAP hauv AKI (mob raum raug mob) kev tshawb fawb siv cov qauv caj ces ntawm CRE recombinase-mediated activation ntawm eGFP-L10a cassette tshwj xeeb hauv nephron, stromal, vascular, lossis lub cev tiv thaiv kab mob thiab pom cov kev hloov pauv sib txawv txuas rau txhua lub cellular compartment tom qab AKI (mob raum raug mobIb.) [29]. Ntau cov noob muaj feem xyuam rau lub raum tubular kev ua haujlwm tau txo qis 24 teev tom qab AKI (mob raum raug mob). Hauv qhov sib piv, cov noob koom nrog hauv kev ua haujlwm los tiv thaiv apoptotic, kev loj hlob ntawm tes, thiab kev txav ntawm tes tau ua kom zoo dua qub. TRAP tsom xam ntawm cov kab mob sib thooj ntawm cov tubules uas tseem ceeb los ntawm qhov raug mob Kim-1(encoded los ntawm Hazel) pom feem ntau ntawm Kim-1- cov hlwb zoo kho tau zoo ob lub lis piam tom qab AKI (mob raum raug mob), txawm hais tias 15 feem pua ​​​​tseem tuav cov lus qhia ntawm Kim-1 thiab tus cim raug mob Sox9 [10], qhia txog lub xeev raug mob tsis tu ncua [30]. Kev tshuaj xyuas Clonal tau qhia tias qhov nthuav dav ntawm Kim-1 qhov zoo clones repopulated puas cov tubules, txhawb tus qauv ntawm kev kho los ntawm dedifferentiation ntawm proximal tubule hlwb, es tsis yog los ntawm ib tug tshwj xeeb qia/progenitor cell pejxeem [30]. Qhov kev hloov pauv ntawm FoxMI tau raug tswj hwm zoo heev hauv Kim-1- cov kab mob zoo sib xws ntawm cov tubules thiab pom tias tsav cov tubule proximal proliferation nyob rau hauv zitro nyob rau hauv ib qho epidermal loj hlob yam receptor-nyob ntawm seb [30]. High-throughput ib leeg-cell mRNA sequencing mus kom ze, tshuaj xyuas tag nrho-cell mRNA sequencing profiles (scRNA-seq) los yog nuclear-localized mRNA transcripts (snRNA-seq), muaj kev txhim kho AKI (mob raum raug mob) kev kawm. Cov txheej txheem no muab kev nkag siab tob molecular rau hauv cov noob qhia ntawm qib ntawm tes thaum ua ke nrog cov txheej txheem kev suav muaj zog, txheeb xyuas cov kab mob sib txawv thiab cov xov tooj ntawm tes thoob plaws hauv lub cev [31,32]. scRNA-seq pib los ntawm kev ncua ntawm ib lub hlwb lossis ib lub nuclei, uas tau sau nrog cov cim cim molecular thiab lysed (Daim duab 2). Cov mRNA tom qab ntawd rov thim rov qab, nthuav dav, thiab ua ntu zus. Ib qho kev tshawb fawb snRNA-seq ntawm ob lub raum raug rau unilateral ureteral obstruction (UUO) tau txheeb xyuas ob qhov tshiab proximal tubule cell pawg 14 hnub tom qab UUO, ib qho uas muaj qhov muaj zog proliferative kos npe, thaum lwm qhov qhia cov noob koom nrog hauv kev mob thiab kev txav ntawm tes, xws li Ccl2, II34, Cxcl, and Dock10 [33].

Cov tib neeg ntawm tes zoo sib xws yog pom tseeb hauv kev tshawb fawb snRNA-seq profileing lub raum raug mob tom qab IRI [34]. Hauv thawj teev tom qab IRI, muaj kev txo qis ntawm cov kab mob ib txwm nyob ze ntawm tubule noob qhia thiab cov lus teb uas muaj cim nrog rau cov noob tam sim ntawd thiab cov cim raug mob HuverI thiab Krt20 [24,25,34]. Los ntawm hnub ob tom qab IRI, ib feem loj ntawm cov tubules ze ze tau pom ib qho kev loj hlob los yog rov ua dua t transcriptional kos npe tus yam ntxwv rau qhov sib txawv proximal tubule hlwb. Txawm li cas los xij, ib qho me me ntawm cov kab mob proinflammatory, profibrotic hlwb, tus cwj pwm los ntawm kev qhia ntawm Vcaml nyob rau hauv feem ntau cov hlwb, thiab coexpression ntawm Cal2 nyob rau hauv ib tug subset, kwv yees kev ua ntawm NF-KB tsev neeg ntawm transcription yam tseem ceeb. Thaum proliferating proximal tubule hlwb txo qis ob lub lis piam tom qab AKI (mob raum raug mob), proinflammatory, profibrotic proximal tubule hlwb nce, qhia txog kev sib txuas ntawm kev kho tubular tsis ua hauj lwm thiab pom cov neeg mob profibrotic cell (Daim duab 1). Interestingly, deconvolution tsom xam ntawm bulk RNA sequencing kev tshawb fawb qhia ib tug zoo xws li cov pejxeem nce raws li lub raum hnub nyoog ib txwm thiab tom qab hloov.

Nyob rau hauv txoj kab nrog txoj kev tshawb fawb tau hais los saum no [34], ib qho kev xaiv ntawm noob caj noob ces tsom rau qhov raug mob ntawm cov tubules uas raug mob plaub lub lis piam tom qab mob me me AKI (mob raum raug mob), siv Krt20-T2A-CRE-ERT2 nas rau daim ntawv lo thiab ntxuav cov kab mob uas raug mob proximal tubules, pom qhov zoo sib xws ntawm cov cellular raug mob phenotype: VcamI/Cal2 ntxiv rau cov neeg raug mob cov tubule cell uas raug mob ntxiv los ntawm qhov muaj zog proinflammatory ( xws li Cal2, Vcam1, Cxcll, /34) thiab profibrotic (egPdgfb, ColAal) transcriptional kos npe, nrog cim ua kom NF-KB, TNF, thiab AP{10}} signaling [35]. Cov kab mob sib kis tau raug mob sib koom sib koom ua ke ntawm kev sib koom ua ke ntawm kev zais zais zais zais (SASP) pom nyob rau hauv lwm lub cev raug mob (Daim duab 1) [35,36]. Nyob rau hauv sib piv rau yav dhau los AKI (mob raum raug mob) kev tshawb fawb [12], tsis muaj qhov tseem ceeb ntawm G2 / M cell voj voog raug ntes nyob rau hauv cov pej xeem no. Ntxiv txoj hmoo-mapping thwmsim ntawm cycling hlwb pom feem ntau ntawm VcamI ntxiv / Cal2 ntxiv rau cov tubules ze ze, nyob rau thaj tsam ntawm corticomedullary, taug qab rov qab mus rau cov cell tubule proliferating thawj hnub tom qab AKI (mob raum raug mob). Txawm li cas los xij, cortical Vuamt plus / Cu2 proximal tubule cells yuav sawv cev rau qhov chaw thib ob ntawm kev raug mob, tsis muaj feem cuam tshuam rau kev rov ua dua tshiab-koom nrog kev kho tubules.

Kev paub txog atlas ntawm qhov raug mob teb rau A unilateral-ischemia reperfusion (UIR) ua scRNA-seq ntawm ntau lub sijhawm cov ntsiab lus los ntawm ib hnub mus rau hnub 14 tom qab UIR tau nthuav tawm cov lus qhia siab hauv cov hlwb raug mob ntawm Sox4 thiab Cd24a, cov noob txheeb xyuas rau lub luag haujlwm hauv lub raum kev loj hlob. [37]. Cov neeg tshiab ntawm tes, 'cov hlwb sib xyaw ua ke,' kuj tau tshaj tawm qhia tias muaj kev sib koom ua ke ntawm cov tubule ze ze (Sl34a7), tuab ascending limb (Umod), los yog sau duct (Agp2) cov cim. scRNA-seq cov ntaub ntawv los ntawm nas folic acid nephropathy thiab UUO qauv qhia tau hais tias txo cov kev qhia ntawm cov cim sib txawv xws li cov neeg nqa khoom nyob rau hauv cov kab mob uas raug mob proximal tubule yog txuam nrog downregulation ntawm cov noob koom nrog hauv cov txheej txheem metabolic, xws li fatty acid oxidation [38]. Lub nuclear receptor Esrra tau raug txheeb xyuas tias yog ib qho tseem ceeb ntawm kev sib txuas ntawm cov tubule sib txawv thiab cov metabolism vim nws ncaj qha tswj cov kev qhia ntawm metabolic thiab proximal tubule-specific noob. Qhov no thiab lwm yam kev tshawb fawb scRNA-seq kuj tseem qhia txog qhov tsis txaus siab yav dhau los ntawm ntau haiv neeg ntawm lub cev tiv thaiv kab mob hauv lub raum [38,39].

Ib qho kev txwv tseem ceeb ntawm tag nrho cov kev sib tham transcriptomics yog qhov tsis muaj cov ntaub ntawv spatial. Novel transcriptomics platforms tam sim no ua rau nws tuaj yeem pom mRNA kev nthuav qhia spatially los ntawm annealing thiab kho cov ntaub so ntswg ncaj qha mus rau qhov tshwj xeeb barcoded probes, imaging cov ntaub so ntswg, thiab ua rov qab transcription nyob rau hauv situ ua raws li kev sojntsuam tso tawm thiab sequencing [40]. Cov ntawv sau ua ntu zus tuaj yeem rov qab los rau hauv cov duab kos duab. Qhov no spatial transcriptomics thev naus laus zis tau tso cai rau thaj chaw tshwj xeeb ntawm ob qhov sib txawv ntawm cov xov tooj ntawm tes ntawm cov tubule ze ze S3 [41] mus rau cortex thiab cov kab txaij ntawm sab nrauv medulla [42].mob raum raug mob) qauv, deconvolution ntawm tus kheej spatial transcriptomic chaw siv scRNA-seq cov ntaub ntawv qhia AKI (mob raum raug mob) cov qauv tshwj xeeb ntawm kev tiv thaiv kab mob hauv lub cev thiab ua kom pom qhov txawv ntawm Af3- qhia txog cov neeg nyob ze ntawm tubule cell, colocalizing nrog neutrophils tom qab IRI [43]. Cov kev tshawb fawb no qhia txog lub peev xwm rau spatial-temporal omics los kwv yees microenvironmental tswj ntawm cov lus teb ntawm tes tom qab AKI (mob raum raug mob).

Cistanche treat kidney disease

Epigenomics

Cov kev pabcuam tshwjxeeb ntawm cov kabmob ntawm cov kabmob sib txawv nyob ntawm qhov kev hloov pauv ntawm cov kabmob ntawm chromatin (piv txwv li, histone methylation thiab acetylation) thiab DNA (piv txwv li, los ntawm cytosine methylation ntawm CpG residues) hauv kev teb rau DNA-binding transcriptional regulators thiab lwm yam. Cov ntaub ntawv pov thawj sib sau ua ke qhia txog lub luag haujlwm tseem ceeb ntawm kev tswj hwm cov txheej txheem epigenetic hauv AKI (mob raum raug mob) thiab kho lub raum [44-46]. Muab qhov kev tshuaj xyuas qhov tob tob zoo heev[44-47], peb tsuas yog qhia luv luv txog cov kev tshawb fawb epigenomics tsis ntev los no hauv AKI (mob raum raug mob) kev tshawb fawb.

Positively charged histone proteins provide the core for packing negatively charged DNA, through electrostatic interactions, into nucleosomes — the structural unit of chromosomes[44]. Modifications to the amino-terminal tails of histones alter the chromatin structure or recruit chromatin modifiers, thus altering gene expression. An unbiased mass spectrometry screen of 63 different histone marks in the healthy kidney revealed widespread histone modifications with a compartment-specific pattern [48]. In this bulk tissue analysis, few histone marks showed a quantitatively significant change >5% tom qab UUO. Interestingly, complementary kev hloov pauv nyob rau hauv sib txawv cov cim ntawm tib amino acid tau qhia, tawm tswv yim ib co lus teb rau AKI (mob raum raug mob) [48].

H3K4me3-cov neeg txhawb nqa tseem ceeb tau muab piv nrog H3K27ac-kos npe txhim kho tom qab AKI (mob raum raug mob) siv chromatin immunoprecipitation thiab tiam tom ntej sequencing (ChIP-seq)[49]. Cov chaw ua kom zoo dua qub tau pom qhov hloov pauv ntau dua hauv cov lus teb rau AKI (mob raum raug mob). Kev hloov kho chromatin ntawm cov chaw ua kom muaj zog tau cuam tshuam nrog kev hloov pauv ntawm cov ntaub ntawv hloov pauv xws li Hnf4a, Gr, thiab Stat3.Hnf4a yog ib qho tseem ceeb ntawm kev hloov pauv hauv qhov kev qhia tshwj xeeb thiab sib txawv ntawm cov cell tubule ze ze [50].Hnf4a khi rau cov ntsiab lus txhim khu kev ua haujlwm hauv ib txwm muaj. proximal tubule cells txo qis hauv cov lus teb rau AKI (mob raum raug mobIb.) [49]. Qhov no yuav pab txhawb rau AKI (mob raum raug mob)-induced dedifferentiation ntawm raug mob proximal tubule cells. Stat3 yog ib qho tseem ceeb transcriptional regulator nyob rau hauv ib tug inflammatory network nrog NF-KB thiab activator protein-1(AP-1) regulatory yam [51].AP-1 txoj kev ua kom muaj kev txuag tau zoo raws li qhov pib. teb rau nas AKI (mob raum raug mob) thiab tib neeg lub raum hloov pauv-txuas nrog IRI [24,25].Stat3 kev koom tes ntawm Junb locus teb rau AKI (mob raum raug mob) qhia txog lub luag haujlwm rau Stat3 inactivation ntawm AP-1 cov khoom sib txuas lus [49]. Tsis tas li ntawd, inhibition ntawm bromodomain thiab ntxiv-terminal (BET)-dependent enhancer activation impaired rov qab tom qab AKI (mob raum raug mob), qhia txog lub luag haujlwm tseem ceeb ntawm kev txhim kho kev muaj zog hauv AKI (mob raum raug mob)kho [49].

ATAC-seq tau dhau los ua cov txheej txheem siv dav tshaj plaws rau kev ntsuas qhov qhib ntawm chromatin thiab kev ua haujlwm ntawm kev tswj hwm thiab sau cov genomic cheeb tsam. Sai sai, ATAC-seq thev naus laus zis tau txav los ntawm kev soj ntsuam cov ntaub so ntswg rhiab nrog tsuas yog 500 lub hlwb, mus rau ib qho kev tshuaj ntsuam xyuas nuclear, thiab feem ntau tsis ntev los no kev soj ntsuam ntawm chromatin lub xeev thiab cov noob qhia hauv tib lub cell [41,52-54]. ATAC-seq siv hyperactive Tn5 transposase txiav ntawm qhib chromatin thiab tag txiav DNA nrog DNA adapters los pab txhawb kev tsim tsev qiv ntawv thiab DNA sequencing (Daim duab 2). Muab tsuas yog ob lub hom phiaj ntawm txhua qhov genome, ATAC cov ntaub ntawv tsis tshua muaj, thiab cov kev tshawb fawb snATAC siv cov txheej txheem suav nrog rau pawg hlwb nrog cov snATAC zoo sib xws thiab koom ua ke nrog tus kheej tsim tawm sc lossis snRNA-seq cov ntaub ntawv. Ib txoj kev tshawb fawb tsis ntev los no qhia txog cellular heterogeneity nyob rau hauv cov neeg laus noj qab nyob zoo tib neeg lub raum cov qauv nrog kev suav nrog snATAC-seq thiab snRNA-seq cov ntaub ntawv teev [55]. Interestingly, txoj kev tshawb no nrhiav tau ib tug subpopulation ntawm VCAM1- qhia proximal tubule hlwb, uas qhia tau hais tias txo cov kev ua ntawm HNF4A thiab nce kev ua ntawm NF-KB tsev neeg, ib feem zoo li proinflammatory, profibrotic raug mob proximal tubule hlwb pom nyob rau hauv nas raum ob peb. lub lis piam tom qab AKI (mob raum raug mob) [34,35,55] ib. Qhov kev nplua nuj ntawm cov neeg ntawm tes no tau nce ntxiv raws sijhawm hauv cov nas laus thiab siab dua hauv tib neeg lub raum mob ntshav qab zib ntau dua li kev tswj hwm kev noj qab haus huv. Yog li, qee cov lus teb ntawm tes zoo li tau khaws cia ntawm cov kab mob sib txawv ntawm lub raum thiab thoob plaws hom. Txawm li cas los xij, qhov twg cov neeg ntawm tes no ua rau muaj hnub nyoog cuam tshuam txog kev ua haujlwm ntawm lub raum thiabmob raumkev vam meej yuav tsum tau tshawb nrhiav ntxiv.

Cell hom kev tshawb nrhiav thiab kev tswj hwm kev kwv yees tau txhim kho los ntawm coanalyzing snRNA-seq thiab snATAC-seq hauv tib lub nucleus[41]. Cov txheej txheem no tsis ntev los no tau siv los ua tus yam ntxwv ntawm tib neeg lub raum noj qab haus huv thiab AKI (mob raum raug mob) thiab CKD biopsies qhia txog kev sib txawv ntawm tes tshiab hauv lub raum ib txwm thiab qhia txog kev raug mob sib piv hauv nas thiab tib neeg AKI (mob raum raug mob), as Well as hloov cov tuab ascending limb cell states characterized by expression of Proml and Dcd2[56]. Tsis tas li ntawd, spatial transcriptomics localized myofibroblasts thiab lub cev tiv thaiv kab mob hauv CKD cov qauv mus rau qhov chaw ntawm kev raug mob tubules [56].

cistanche restore impaired kidney function

Cistanche restore lub raum tsis ua hauj lwm


Proteomics thiab metabolomics

Kev kawm txog cov protein thiab cov metabolites hauv ntshav, zis, thiab cov ntaub so ntswg raum siv gel electrophoresis thiab loj spectrometry ntxiv cov cuab yeej transcriptomic thiab epigenomic. Mass spectrometry tuaj yeem txheeb xyuas thiab txheeb xyuas cov macromolecules (xws li cov proteins) thiab cov cellular metabolites nyob rau hauv cov ntaub so ntswg complex, ntsuas cov khoom sib txawv ntawm cov khoom ntawm cov molecules thaum ionized thiab raug rau cov hlau nplaum lossis hluav taws xob (Daim duab 2) [57]. Ntau cov kev tshawb fawb proteomics tau raug coj mus rau kev txheeb xyuas biomarkers rau AKI (mob raum raug mob)(kev tshuaj xyuas zoo nyob rau lwm qhov[57-59]). Piv txwv li, urinary nqaij inhibitor metalloproteinase-2(TIMP2) thiab IGF-binding protein-7(IGFBP7) qib tau pom tias yuav kwv yees txog kev tuag thiab lub raum tsis ua haujlwm hauv cov neeg mob hnyav nrog AKI (mob raum raug mobIb.) [60]. Kev kho mob ntawm TIMP2 thiab IGFBP7 cov neeg mob sib koom ua ke nrog kev txhawb nqa kev ntsuas raws li Kab Mob Raum Txhim Kho Ntiaj Teb Cov txiaj ntsig (KDIGO) cov lus qhia rau cov neeg mob uas muaj kev pheej hmoo siab rau AKI(mob raum raug mob) txo AKI (mob raum raug mob) kev loj hlob hauv thawj 72 teev tom qab kev phais mob plawv, tab sis tsis cuam tshuam rau kev tuag thiab xav tau kev kho lub raum hloov [61]. Cov txiaj ntsig thiab kev tshawb pom los ntawm lwm cov kev tshawb fawb biomarker tau txhawb nqa; Txawm li cas los xij, qhov zoo tshaj plaws biomarker lossis ntau dua biomarker vaj huam sib luag rau AKI (mob raum raug mob)Kev soj ntsuam kev pheej hmoo, tsom rau AKI (mob raum raug mob)kev tiv thaiv, kev kuaj mob ua ntej, thiab tej zaum txawm tias cov kev qhia kho mob hauv kev kho mob niaj hnub tseem tsis tau txheeb xyuas.

Dhau li ntawm kev tsav tsheb kom zoo AKI (mob raum raug mob) biomarkers, proteomics kuj tuaj yeem siv los nug AKI (mob raum raug mobpathophysiology (62). Kev tshawb fawb ua ntej ntawm cisplatin-induced AKI (mob raum raug mob)qhia txog qhov tsis muaj zog ntawm kev sib raug zoo ntawm transcriptome thiab proteome hauv lub raum raug mob [63]. Txoj kev tshawb no qhia tias qhov tsis sib xws ntawm ob txoj hauv kev tau tsav los ntawm kev hloov pauv ntawm cov protein nyob rau hauv cov khoom sib txuas ntxiv, piv txwv li, hauv cov txheej txheem ntxiv [63]. Interestingly, qhov sib txawv ntawm RNA thiab protein qhia tau muaj kev cuam tshuam nrog kev raug mob hnyav raws li qhia los ntawm cov ntshav creatinine thiab ntshav urea nitrogen theem [63]. Qhov no qhia txog qhov tseem ceeb ntawm kev hloov pauv tom qab hloov pauv hauv AKI (mob raum raug mob)teb.

Tsis ntev los no, nyob ze-ib leeg-cell proteomics profiling, uas ua rau kom muaj nuj nqis proteomic ntsuas los ntawm tsawg li 10 mus rau 100 laser ntes microdissected raum hlwb, tau siv los txheeb xyuas cov proteins tshwj xeeb rau glomerular thiab cov tubular sib thooj hauv lub raum noj qab haus huv [64] . Qee qhov feem ntau enriched compartment-specific proteins correlated zoo nrog kev qhia ntawm cov gene coj nyob rau hauv lub podocyte thiab lub proximal tubule pawg ntawm ib tug scRNA-seq cov ntaub ntawv teev, feem. Tsis tas li ntawd, ntau tshaj 40 cov cim protein tuaj yeem tshawb pom ib txhij ntawm ib ntu ntawm cov ntaub so ntswg los ntawm kev ntsuas huab hwm coj cytometry (IMC), yog li tso cai rau kev kawm txog cov proteome hauv cov ntsiab lus spatial [65]. IMC ntawm cov tib neeg lub raum noj qab nyob zoo tau qhia txog kev npaj txhij txog ntawm cellular heterogeneity thiab txheeb xyuas qhov tsis tshua muaj megalin/aquaporin-1/vimentin (Lrp2/Aqp1/Vim)-zoo cell type uas muaj feem cuam tshuam txog kev raug mob (Vim ntxiv) cov tubule ze ze (Lrp2 ntxiv / Aqp1 ntxiv rau) cell xeev [65]. Kev siv cov thev naus laus zis no rau AKI (mob raum raug mob) kev tshawb fawb yuav muab kev nkag siab tseem ceeb rau hauv thaj chaw proteomic ntawm kev raug mob thiab kho.

Txoj kev tshawb fawb ntawm lub raum metabolome (molecules me dua 1500 Da [62]) tau ntxiv kev nkag siab txog AKI (mob raum raug mob) pathophysiology.

Metabolomic

Profileing ntawm cov ntaub so ntswg raug mob siv cov kua chromatography-mass spectrometry coj mus rau qhov kev tshawb pom tias de neo nicotinamide adenine dinucleotide (NAD plus ) synthesis yog impaired hauv AKI (mob raum raug mobIb.) [66]. Downregulation ntawm mitochondrial biogenesis regulator PGCla hauv AKI (mob raum raug mob) ua rau hauv zos NAD ntxiv rau depletion, thaum PGC1 tshaj-qhia tau nce raum NAD ntxiv rau qib thiab txo AKI (mob raum raug mobIb.) [66]. Cov tshuaj ntsuam xyuas cov zis tsis txaus ntseeg kuj tau pom tias nce qib ntawm NAD ntxiv rau precursor quinoline hauv cov zis ntawm cov nas tom qab IRI [67] ua los ntawm kev txo qis ntawm lub raum quinoline phosphoribosyltransferase (QPRT), ib qho tseem ceeb enzyme nyob rau hauv de novo NAD ntxiv synthesis [67]. Txo lub raum QPRTlevels tau txuam nrog AKI siab dua(mob raum raug mob) kev nyuaj siab [67]. Kev kho qhov ncauj nicotinamide khaws cia AKI (mob raum raug mob)-induced lub raum NAD ntxiv rau biosynthetic deficiency nyob rau hauv nas, thiab ib theem me me 1 kev sim tshuaj ntsuam xyuas tau qhia tias muaj peev xwm raum tau txais txiaj ntsig ntawm kev kho nicotinamide hauv cov neeg mob uas tau phais plawv [67]. Ib txoj kev tshawb nrhiav metabolomics ntawm tib neeg lub raum hloov pauv biopsies, ua ntej thiab tom qab reperfusion, pom qhov sib txawv ntawm cov metabolic profile ntawm kev hloov pauv nrog rau yav tom ntej qeeb graft muaj nuj nqi piv nrog kev hloov pauv yam tsis muaj kev ncua sij hawm graft [68]. Kev hloov pauv nrog rau yav tom ntej ncua kev ua haujlwm graft tau tshwm sim los ntawm kev pheej hmoo ATP / GTP catabolism, tawm tswv yim txog kev kho kom zoo thaum ntxov ntawm lub zog homeostasis raws li lub hom phiaj kho hauv AKI (mob raum raug mob) tiv thaiv [68]. Mass spectrometry imaging (MSI) yog cov txheej txheem muaj zog siv los ua kom pom qhov sib faib ntawm cov metabolites, proteins, lossis lipids, nrog kev daws teeb meem ntawm cellular thiab subcellular [69]. MSI tsom xam ntawm cov raum raug mob pom lipidomic e siv ch coll .x7rr kom sib txawv ntawm me thiab hnyav ischemia thaum ntxov li 2 teev tom qab raug mob [70,71].

Cov lus xaus thiab kev pom

Muaj omics technologies tau ua rau peb nkag siab txog AKI (mob raum raug mob) thiab kho. Kev koom ua ke lossis ib txhij tau txais ntawm cov ntaub ntawv sib txawv omics yuav ntxiv kev nkag siab ntxiv rau AKI (mob raum raug mob), thiab corroborative tshawb pom los ntawm orthogonal mus kom ze yuav muab kev ntseeg siab ntxiv rau cov txheej txheem txheeb xyuas. Cov kev nkag siab tshiab, cov cuab yeej, thiab cov ntaub ntawv xov xwm tau txais txiaj ntsig nrog kev nqis peev los ntawm NIDDK hauv ntau lub koom haum loj suav nrog Txoj Haujlwm Kev Kho Mob Rau Raum thiab Kev Txhim Kho Rau Raum. Qhov kev sib tw loj ntawm lub sijhawm no ntawm 'cov ntaub ntawv loj" yog los txiav txim siab txog cov txheej txheem lom neeg los ntawm cov ntaub ntawv nyuaj heev rau kev ywj pheej nkag mus rau cov ntaub ntawv no los ntawm cov neeg siv-phooj ywg saib thiab cov ntaub ntawv tsom xam platforms, thiab thaum kawg, los txhais peb cov kev nkag siab ntawm pathophysiologic nce rau hauv kev kuaj mob thiab Cov tswv yim kho mob uas txhim kho kev saib xyuas neeg mob thiab AKI (mob raum raug mob) qhov tshwm sim.

Tshaj tawm ntawm kev sib tw txaus siab

Cov kws sau ntawv tshaj tawm cov kev nyiam nyiaj txiag hauv qab no / kev sib raug zoo ntawm tus kheej uas tej zaum yuav suav tau tias yog qhov muaj peev xwm sib tw: APMis tus kws pab tswv yim txog kev mob raum rau tib neeg cov kab mob rau Novartis, eGenesis, Aviva, thiab Trestle Biotherapeutics.

Kev lees paub

Peb thov zam txim rau txhua tus kws tshawb fawb uas nws txoj haujlwm tsis tuaj yeem tham txog vim qhov chaw txwv. Peb ua tsaug rau Dr. Pietro E.Cippà rau qhov kev nyeem ntawv tseem ceeb ntawm cov ntawv sau. LMS Gerhardt tau txais kev txhawb nqa los ntawm German Research Foundation (DFG), Lub teb chaws Yelemees nrog cov nyiaj pab kawm ntawv qib siab (GE 3179/1-1). Ua haujlwm hauv AP McMahon lub chaw kuaj mob tau txais kev txhawb nqa los ntawm NIDDK, Tebchaws Meskas (DK126024,54364,126925) thiab ChanZuckerberg Initiative, Tebchaws Meskas (CZIF2019-002430).


kidney disease : acute kidney injury

Cov ntaub ntawv

Cov ntaub ntawv tshwj xeeb uas txaus siab, luam tawm nyob rau lub sijhawm tshuaj xyuas, tau hais meej raws li:

1. Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW:Mob raum raug mob, kev tuag, kev nyob ntev, thiab cov nqi hauv tsev kho mob.JASN (J Am Soc Nephrol) 2005, 16:3365-3370.

2. Mehta RL, Cerda J, Burdmann EA, Tonelli M, Garcia-Garcia G, Jha V, Susantitaphong P, Rocco M, Vanholder R, Sever MS, et al: International Society of Nephrology's 0by25 teg num raumob raum raug mob(zero Preventable deaths by 2025): ib tug human rights case for nephrology.Lancet 2015, 385:2616-2643.

3. Hsu RK, Hsu CY: Lub luag hauj lwm ntawmmob raum raug mobnyob rau hauv mob 3. H raum kab mob. Semin Nephrol 2016, 36:283-292.

4. Chawla LS, Eggers PW, Star RA, Kimmel PL:Mob raum raug mobthiab mob raum mob raws li interconnected syndromes. N Engl J Med 2014,371:58-66.

5. Legrand M, Tswb S, Fomi L, Joannidis M, Koyner JL, Liu K, 5, 1; Cantaluppi V: Pathphysiology ntawm COVID-19-sociatedmob raum raug mob. Nat Rev Nephrol 2021.https://doi.org/10.1038/s41581-021-00452-0. Qhov kev tshuaj xyuas no muab cov ncauj lus ntxaws ntxaws ntawm cov ntaub ntawv tam sim no ntsig txog COVID-19- cuam tshuammob raum raug mob.

6. Zuk A, Bonventre JV: Kev nce qib tsis ntev los no ntawmmob raum raug mob6. 2 thiab nws qhov tshwm sim thiab cuam tshuam rau cov kab mob raum ntev. F Curr Opin Nephrol Hypertens 2019,28:397-405. Qhov kev tshuaj xyuas zoo no qhia txog cov txheej txheem pathophysiologic hauv qab ntawm kev hloov pauv ntawm mob raum mob raum mob thiab qhia txog lub luag haujlwm ntawm mitochondrial tsis ua haujlwm, o, senescence, thiab cell tuag hauv cov txheej txheem no.

7. Saran R, Robinson B, Abbott KC, Agodoa LYC, Bragg Gresham J, Balkrishnan R, Bhave N, Dietrich X, Ding Z, Eggers PW, et al: US renal data system 2018 txhua xyoo cov ntaub ntawv tshaj tawm: kev kis kab mob raum hauv Tebchaws Meskas. AmJ Raum Dis 2019,73:A7-A8.US Renal Data System 2018 Daim Ntawv Qhia Txhua Xyoo muaj los ntawm: https://www.usrds.org/media/2282/2018_volume{{9} }ckd_hauv_the_us.pdf. (Tau txais 11 Lub Plaub Hlis 2021).

8. Ferenbach DA, Bonventre JV: Mechanisms of maladaptive 8. kho tom qab AKI (mob raum raug mob) ua rau kom ceev lub raum laus thiab CKD. Nat Rev Nephrol 2015,11:264-276.

9. Kusaba T, Lalli M, Karmann R, Kobayashi A, Humphreys BD: 9.Differentiated raum epithelial hlwb kho cov raug mob proximal tubules. Proc Natl Acad Sci US A 2014,111:1527-1532. 10. Kumar S, Liu J, Pang P, Krautzberger AM, Reginensi A,

10. Akiyama H, Schedl A, Humphreys BD, McMahon AP: Sox9 activation highlights a cellular pathway of renal repair in the acutely hurt mammalian heart.Cell Rep 2015,12:1325-1338.

11. Kang HM, Huang S, Reidy K, Han SH, Ching F, SusztakK: Sox9 zoo progenitor cells ua lub luag haujlwm tseem ceeb hauv lub raum tubule epithelial regeneration hauv nas. Cell Rep 2016,14:861-871.

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19. Papaioannou VE: Tsev Neeg T-box gene: lub luag haujlwm tshwm sim hauv kev loj hlob, qia hlwb, thiab mob qog noj ntshav. Kev txhim kho 2014.141:3819-3833.

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