Morphological Analyzes Ntawm Nephrin Expression nyob rau hauv Progressive Glomerulonephropathy

Hu rau:joanna.jia@wecistanche.com/ WhatsApp: 008618081934791

Abstract:

Nyob rau hauv txoj kev tshawb no, peb tsom mus rau nephrin, ib qho ntawm cov molecules tseem ceeb nyob rau hauv lub slit diaphragm ntawm podocytes, txawm hais tias muaj cov ntaub ntawv qhia txog nws cov kev qhia nyob rau hauv tib neeg thiab nas, lawv muaj nyob rau hauv ntau marmosets tsis tau qhia. Peb tau tshawb xyuas nephrin qhia thiab kev hloov pauv hauv glomeruli, nyob ntawm qhov kev loj hlob ntawm kev loj hlob ntawm glomerulonephropathy hauv cov marmosets. Kaum cuaj hom marmosets ntawm ob mus rau kaum xyoo ntawm lub hnub nyoog raug soj ntsuam. Lub raum tau kuaj xyuas los ntawm microscopy nrog hematoxylin thiab eosin thiab immunohistochemical staining rau nephrin. Cov kab mob tau muab faib ua peb qib raws li lub raum qhov mob grading system qhia yav dhau los. Lub cheeb tsam nephrin-zoo tau ntsuas los ntawm kev tshuaj ntsuam morphometric, thiab nephrin-zoo piv tau raug xam. Nephrin qhia tau pom raws lub glomerular capillary voj nyob rau hauv ib tug nruam linear qauv nyob rau hauv lub raum kab mob qib 0 mus rau 2 thiab ib tug discontinuous linear los yog coarse granular qauv nyob rau hauv qib 3. Nephrin qhia feem ntau yuav txo qis nyob rau hauv cov qib ntawm lub raum mob. . Kev hloov pauv hauv nephrin qhia tau hais tias ua lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm lub raum kab mob.

Ntsiab lus:nephrin ua, marmoset,glomerulonephropathy mob ntshav qab zib, raum, kab mob

suab puam cistanche cov txiaj ntsigthiabCistanche cogyog qhov zoo rauraum

Taw qhia

Spontaneous progressive glomerulonephropathy nyob rau hauv ntau marmosets (Callithrix jacchus) paub tias tshwm sim nquag pib thaum muaj hnub nyoog ob xyoos, nrog rau qhov mob hnyav zuj zus nrog lub hnub nyoog. Peb yav dhau los tau tshaj tawm cov kab mob tseem ceeb thiab kev loj hlob ntawm nephropathy hauv cov kab mob marmosets1. Kev hloov pauv ntawm glomerular theem pib ntawm nephropathy yog qhov tshwm sim los ntawm kev ua haujlwm ntawm cov txheej txheem podocyte ko taw thiab ib nrab thickening ntawm glomerular qab daus daim nyias nyias, xav tias yuav ua rau cov protein tawm ntawm lub glomeruli, thiab tuaj yeem pom los ntawm ultramicroscopy tab sis tsis yog los ntawm lub teeb microscopy1-3. Tsis tas li ntawd, immunoglobulin plays lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm nephropathy1, 2. IgM tau tso rau hauv mesangium thaum ntxov ntawm glomerulonephropathy, thiab tom qab thawj qhov tso tawm ntawm IgM, thaj chaw tso nyiaj nthuav dav mus rau tag nrho glomerulus, thiab IgA thiab IgG yog. tso nrog kev vam meej2. Hyaline casts tawm tswv yim tawm ntawm cov protein los ntawm glomeruli tuaj yeem pom los ntawm lub teeb pom kev zoo nrog kev loj hlob ntawm glomerulonephropathy4. Proteinuria exacerbates qhov kev loj hlob ntawm tubulointerstitial lesions nyob rau hauv ntau marmosets4, xws li nyob rau hauv tib neeg 5, 6, thiab, nyob rau hauv ib tug tsis ntev los no txoj kev tshawb no ntawm lub glomeruli, proteinuria yuav induced los ntawm cov teeb meem ntawm lub slit diaphragm, yog li txuas cov txheej txheem ko taw (pedicels) ntawm podocyte. Lub diaphragm slit yog ib qho intercellular junctional complex tam sim no ntawm cov txheej txheem ko taw uas nyob ib sab, thiab qee cov molecules ntsig txog nws tsim tau raug txheeb xyuas 3. Ib qho kev txo qis hauv cov lus qhia ntawm cov molecules los yog kev ua haujlwm tsis zoo ntawm lub qhov diaphragm tau xav tias yuav cuam tshuam nrog kev nce qib ntawm proteinuria 3. Nephrin, ib qho ntawm cov molecules tseem ceeb uas tau nthuav tawm nyob rau hauv slit diaphragm ntawm podocytes, yog glycoprotein uas muaj 1241 amino acids thiab yog ib tug paub zoo biomarker siv los saib xyuas qhov tsis meej ntawm slit diaphragms7-10. Molecules muaj feem xyuam rau cov kab mob slit diaphragms tsis tau kawm hauv nephropathy ntawm cov marmosets, txawm hais tias kev hloov pauv ntawm cov txheej txheem podocyte ko taw thiab kev loj hlob ntawm cov proteinuria paub tias tshwm sim hauv lawv. Ntxiv mus, muaj cov lus ceeb toom txog kev qhia ntawm nephrin hauv tib neeg thiab nas 7-12 tab sis tsis nyob hauv marmosets. Yog li, peb tau tshawb xyuas nephrin qhia hauv glomeruli thiab kev hloov pauv hauv nephrin qhia, nyob ntawm seb qhov kev mob tshwm sim, los ntawm kev tshuaj ntsuam immunohistochemical.

ceg tcm

Cov ntaub ntawv thiab cov txheej txheem

Tsiaj

Txoj kev tshawb no tau pom zoo los ntawm Pawg Saib Xyuas Tsiaj Tsiaj thiab Siv Pawg ntawm Central Institution for Experimental Animals (CIEA; Kawasaki, Nyiv) thiab tau ua raws li Txoj Cai Tswjfwm Tsiaj Tsiaj ntawm CIEA raws li Cov Txheej Txheem rau Kev Coj Zoo ntawm Animal Experiments (Science Council of Japan, 2006). Kaum cuaj hom marmosets (11 txiv neej thiab 8 tus poj niam) los ntawm CLEA Nyiv Inc. (Tokyo, Nyiv) raug soj ntsuam. Lawv muaj hnub nyoog li ntawm 2 mus rau 10 xyoo thaum lub sij hawm necropsy. Cov tsiaj tau muab tso rau hauv tawb hauv chav tsiaj uas khaws cia ntawm qhov kub ntawm 26 ± 3 degree thiab av noo ntawm 55 ± 20 feem pua. Lawv tau pub nrog LCMS-1M (CLEA Nyiv Inc., Tokyo, Nyiv) thiab cov kais dej. Cov tsiaj txhu tau muab txi rau tib neeg raws li kev siv tshuaj loog nrog pentobarbital sodium vim muaj ntau yam ua rau moribund (xws li syntexis, curvature ntawm lumbar vertebrae, mandibular joint dislocation, thiab lwm yam). Kev kuaj zis tsis tau ua vim tsis tuaj yeem kuaj zis.

Histopathology

Covlub raumtau perfused nrog saline, ua raws li 4 feem pua ​​​​ntawm paraformaldehyde, thiab tom qab ntawd kho hauv 10 feem pua ​​​​ntxhiab tsw-buffered formalin rau kev soj ntsuam microscopic. Cov qauv tau muab tso rau hauv paraffin, ntu ntawm 5 μm thickness, thiab stained nrog hematoxylin thiab eosin (HE). Cov kab mob tau muab cais ua glomerular, tubular, thiab interstitial lesions raws li cov qauv luam tawm 1. Qib nephropathy tau muab faib ua plaub pawg: qib 1 (3 tug txiv neej thiab 1 poj niam), qib 2 (3 txiv neej thiab 5 tus poj niam), qib 3 (1 txiv neej thiab 3 poj niam), thiab qib 4 (3 txiv neej) (Table 1).

Rau immunohistochemistry, monoclonal antibody tiv thaiv lub extracellular domain ntawm tib neeg keeb kwm.nephrin ua(1:1,000, Nephring{{0}}, Santa Cruz Biotechnology, Inc., Dallas, TX, USA) tau siv los ua thawj cov tshuaj tiv thaiv kab mob. Cov 5-μm seem tau deparaffinized, rehydrated, kho nrog 3 feem pua ​​hydrogen peroxide nyob rau hauv chav tsev kub rau 5 min, thiab ces rhuab nyob rau hauv ib tug autoclave ntawm 121 degree rau 20 min nyob rau hauv lub hom phiaj retrieval tov (pH 6.0, Dako, Glostrup, Denmark). Tom qab txias, cov seem tau incubated nrog thawj cov tshuaj tiv thaiv ntawm 4 degree thaum hmo ntuj. Peroxidase-conjugated anti-nas thiab anti-luv IgG polymer (Histofine Simple Stain Rat MAX-PO(MULTI), Nichirei Bioscience Inc., Tokyo, Nyiv) tau siv los ua cov tshuaj tiv thaiv thib ob rau cov txheej txheem polymer-based method13. Cov ntu tau tsim nrog cov tshuaj tiv thaiv polymer thib ob ntawm chav tsev kub rau 30 min thiab cov khoom siv hluav taws xob tau pom pom siv 3,3'-diaminobenzidine ua chromogen. Cov tshuaj tiv thaiv tau ua nrog hematoxylin. Rau kev tswj tsis zoo, thawj cov tshuaj tiv thaiv tau raug tshem tawm.

Morphological tsom xam

Rau kev soj ntsuam morphological, glomeruli nrog glomerular hilum raug xa mus rau kev kuaj xyuas, thiab 16 txog 28 glomeruli raug ntes ntawm txhua tus swb (Table 1) siv tag nrho cov swb scanner (Aperio AT2, Leica Microsystems Inc., Buffalo Grove, IL, USA) thiab cov kab mob sib kis tau swb saib software (Aperio ImageScope, Leica Microsystems Inc.) ntawm tib qhov kev daws teeb meem thiab cov duab loj.Nephrin-zoo thiab tag nrho cov glomerular thaj chaw tau suav nrog cov duab tsom xam software (Image-Pro V10, Mediacybenetics Inc., Rockville MD, USA) los ntawm kos ib cheeb tsam ntawm kev txaus siab nyob ib ncig ntawm lub glomerulus, raws li daim ntawv tshaj tawm yav dhau los14. Tag nrho thaj chaw glomerular tau txhais tias yog thaj chaw uas tuaj yeem paub qhov txawv ntawm cov xim dawb tom qab. Cov xim pib rau kev xamnephrin ua- thaj chaw zoo raug txiav txim siab raws li txhua qhov xwm txheej staining. Cov theem pib rau liab, ntsuab, thiab xiav yog 37–67, 31–77, thiab 32–88, raws li. Tus nephrin-zoo piv tau suav los ntawm kev faib cov kev ntsuas ntawm covnephrin ua- thaj chaw zoo tshaj qhov chaw glomerular. Kev txheeb xyuas kev txheeb xyuas tau ua tiav siv qhov kev xeem Jonckheere (theem tseem ceeb: 5 feem pua, kev sim ib sab) los ntsuas qhov sib txawv ntawm qib nephropathy thiab kev qhia ntawmnephrin ua.

costanche

Cov txiaj ntsig

Cov qhab nia ntawm kab mob thiab qib ntawm cov kab mob hauv lub raum tau pom nyob rau hauv Table 1. Zoo ib yam li tau tshaj tawm hauv peb daim ntawv tshaj tawm thawj zaug 1, qib kab mob tau nce ntxiv raws li hnub nyoog thiab tsis muaj qhov sib txawv ntawm poj niam txiv neej. Cov txiaj ntsig ntawm immunohistochemical staining ntawmnephrin uamuaj nyob rau hauv daim duab 1, thiab covnephrin ua-zoo piv yog qhia nyob rau hauv daim duab 2 thiab Table 1. Ntawm cov qhab nia thiab qib nyob rau hauv Table 1, lub raum lesion qib, muab los ntawm tag nrho cov qhab nia ntawm txhua qhov mob raum, thiab hyaline cast qhab nia tau siv los sib piv nrog covnephrin ua-zoo piv (Daim duab 2 thiab 3). Cov xwm txheej ntawm tus kheej hauv Table 1 tau pom nyob rau hauv qhov kev txiav txim siab ntawm lub raum mob qib. Nephrin qhia tau pom nrog rau lub glomerular capillary voj nyob rau hauv ib tug nruam linear qauv hauv qib 0 mus rau 2 (Fig. 1A–C) thiab ib tug discontinuous linear los yog coarse granular qauv nyob rau hauv qib 3 (Fig. 1D). Hauv cov qauv tswj tsis zoo, tsis muaj cov tshuaj tiv thaiv zoo raunephrin uatau pom nyob rau hauv tej qhov chaw.

Qhov sib piv ntawm covnephrin ua-positive piv rau lub raum lesion qib yog qhia nyob rau hauv daim duab 2. Nyob rau hauv lub raum lesion qib 0, qhov nruab nrab ± standard deviation (SD) ntawm covnephrin ua-zoo piv yog 5.66 ± 1.18 feem pua, thiab qhov siab tshaj plaws, yam tsawg kawg nkaus, thiab nruab nrab qhov tseem ceeb yog 6.84 feem pua, 4.27 feem pua, thiab 5.76 feem pua. Hauv qib 1, qhov nruab nrab ± SD yog 3.99 ± 1.61 feem pua, thiab qhov siab tshaj plaws, yam tsawg kawg, thiab qhov nruab nrab yog 5.69 feem pua, 1.19 feem pua, thiab 4.35 feem pua. Hauv qib 2, qhov nruab nrab ± SD yog 3.82 ± 2.25 feem pua, thiab qhov siab tshaj plaws, yam tsawg kawg, thiab qhov nruab nrab yog 6.71 feem pua, 1.58 feem pua, thiab 3.49 feem pua. Hauv qib 3, qhov nruab nrab ± SD yog 2.52 ± 1. Ua ke, qhov sib txawv ntawm tus kheej hauv nephrin qhia tau me me hauv qib 0, tab sis loj hauv qib 1 lossis siab dua, thiab qhov kev qhia tsis zoo tau raug kuaj pom tsis zoo.NephrinKev nthuav qhia yuav txo qis nyob ntawm qib ntawm lub raum mob (Daim duab 2). Muaj qhov sib txawv me ntsis ntawm lub raum mob qib thiabnephrin ua-zoo piv raws li kev xeem Jonckheere (p=0.0166). Cov qhab nia hyaline cast nyob rau hauv kev sib piv rau lub raum lesion qib yog qhia nyob rau hauv daim duab 3. Nyob rau hauv cov ntaub ntawv uas muaj ib tug hyaline cast qhab nia ntawm 0, qhov nruab nrab ± SD ntawm nephrin zoo piv yog 5.40 ± 1.32 feem pua, nyob rau hauv cov qhab nia 1 mob, nws yog 4.10. ± 1.70 feem pua, thiab hauv cov qhab nia 2, nws yog 3.37 ± 1.98 feem pua. Muaj qhov sib txawv qis dua ntawm cov qhab nia hyaline cast thiab nephrin zoo piv raws li kev sim Jonckheere (p=0.0654).

Kev sib tham

Kev txo qis hauv nephrin tau cuam tshuam nrog kev loj hlob ntawm lub raum mob thaum lub sij hawm kev loj hlob ntawm marmoset glomerulonephropathy. Cov tshuaj tiv thaiv-nephrin antibody siv nyob rau hauv txoj kev tshawb no tau lees paub lub extracellular domain ntawm N-terminal sab. Qhov no extracellular domain interacts nrog NEPH1 molecules thiab tsim ib tug zipper zoo li qauv nyob rau hauv lub slit diaphragm15. Localization ntawm nephrin nyob rau hauv ib txwm glomeruli yog raws lub glomerular capillary voj thiab staining qauv yog ib tug linear qauv ntawm nruam zoo granules ob leeg nyob rau hauv nas thiab tib neeg11, 12, 16-18. Cov staining ua nyob rau hauv txoj kev tshawb no yog tsim nyog; uas tau lees paub los ntawm kev soj ntsuam tias cov phab ntsa capillary nyob rau hauv kev sib cuag nrog thaj tsam mesangial tsis stained, thaum cov neeg nyob rau hauv kev sib cuag nrog cov podocytes. Raws li cov xwm txheej txawv txav, xws li nephrotic syndrome hauv tib neeg lossis puromycin aminonucleoside nephrosis hauv nas, nephrin staining qauv hauv glomeruli yog tsis tu ncua thiab ntxhib granular, thiab kev siv ntawm immunohistochemical staining tsis muaj zog dua li hauv ib txwm glomeruli11, 16 hauv txoj kev tshawb no, , tus qauv nephrin qhia hauv qib 0 mus rau 2 yog qhov qub; Txawm li cas los xij, tus qauv staining hauv qib 3 tau muab piv rau qhov txawv txav. Hauv kev tshawb nrhiav yav dhau los ntawm glomerular nephrin qhia hauv Crl: CD (SD) nas nrog cov kab mob hloov tsawg, nephrin qhia tau zoo lawm, txawm hais tias cov txheej txheem podocyte ko taw pom tau tias muaj kev cuam tshuam nyob rau hauv electron microscopy uas tsis muaj qhov pom tseeb hloov pauv tau pom nyob rau hauv lub teeb microscopy18. Hauv cov kab mob hauv lub raum ntawm cov nas, cov kab mob nephropathy mob ntev (CPN), nws tau pom tias albuminuria nrog rau CPN thaum ntxov yuav ua rau muaj kev hloov pauv tsawg dua hauv glomerular permeability los ntawm qhov tsis ua haujlwm rau reabsorb albumin los ntawm proximal tubules19. Hauv tib neeg, muaj qee qhov kev tshawb fawb txog kev txo qis ntawm nephrin qhia nyob rau hauv me me hloov10 los yog nyob rau hauv lwm yam kab mob raum14, 16. Ntawm qhov tod tes, tau muaj ib daim ntawv qhia txog qhov tsis zoo nephrin qhia nyob rau hauv tsawg heev hloov nephrosis20. Lub xub ntiag los yog tsis muaj kev hloov pauv hauv kev qhia ntawm nephrin hauv kev hloov pauv nephrotic tsawg heev tseem tab tom tham. Nyob rau hauv qhov tseeb, nws yog ib qho nyuaj kom paub meej tias qhov nce los yog txo cov tshuaj tiv thaiv antibody ntawm nephrin los ntawm kev pom kev pom nyob rau hauv marmoset nephropathy, tab sis nws muaj peev xwm mus ntes tau qhov kev hloov nyob rau hauv tag nrho lub raum los ntawm cov duab tsom xam. Peb qhov kev tshawb fawb qhia tias qhov txawv txav ntawm qhov diaphragms ntawm lub glomerulus tuaj yeem cuam tshuam nrog kev loj hlob ntawm nephropathy hauv cov marmosets vim qhov txo qis hauv nephrin. Kev hloov pauv ntawm qhov zoo staining qauv ntawm nephrin, los ntawm linear mus rau granular qauv, tau tshaj tawm nyob rau hauv ib tug nas tsiaj qauv ntawm cov kab mob nephrotic thaum lub sij hawm txoj kev loj hlob ntawm lesion11, 16, 21. Ib qho kev sib koom ntawm kev txawv txav ntawm lub slit membrane thiab proteinuria muaj nquag tshaj tawm 22, 23; Yog li, nws tau raug kwv yees tias cov proteinuria tuaj yeem tshwm sim los ntawm kev ua haujlwm ntawm lub diaphragm. Hauv peb txoj kev tshawb fawb ntawm marmoset nephropathy, qhov kev loj hlob ntawm glomerular protein permeability vim qhov kev ua haujlwm ntawm lub diaphragm tsis ua haujlwm yuav tshwm sim vim hais tias cov yam ntxwv ntawm hyaline casts tau pom tsuas yog hauv cov xwm txheej tsis muaj kev hloov pauv ntawm tubulointerstitial. Hauv txoj kev tshawb no, tsis muaj qhov sib txawv tseem ceeb ntawm cov qhab nia ntawm morphological hloov ntawm hyaline casts thiab txo qis hauv nephrin qhia. Txawm li cas los xij, nephrin qhia yuav txo qis nyob ntawm qhov qhab nia hyaline cam khwb cia, uas yog qhov qhia txog cov protein tawm los ntawm glomerulus.

Hauv peb qhov kev tshawb nrhiav yav dhau los, effacement ntawm cov txheej txheem ko taw tau pom nyob rau theem pib ntawm marmoset nephropathy thiab thaj chaw cuam tshuam ntawm ko taw tau nthuav dav nyob ntawm qhov mob raum qib 1. Table 2 qhia txog kev sib raug zoo ntawm qhov txo qis ntawm nephrin hauv txoj kev tshawb no thiab cov kev tshawb pom ntawm electron microscopy rau txhua qib ntawm lub raum mob los ntawm kev kawm dhau los. Effacement yog xav tias yog vim muaj kev puas tsuaj hauv actin cytoskeleton ntawm cov txheej txheem ko taw24. Nephrin yog dephosphorylated thaum lub slit membrane yog tsim, thiab nws khi rau actin los ntawm CD2AP thiab podocin25, 26. Thaum ib tug slit diaphragm raug mob, nephrin molecules ua clustered, inducing nephrin phosphorylation, actin polymerization, thiab effacement ntawm ko taw txheej txheem26. Nephrin phosphorylation kuj tshwm sim sai tom qab induction ntawm ko taw txheej txheem effacement nyob rau hauv tus qauv protamine sulfate nyob rau hauv nas27. Nephrin yog glomerular adhesion protein txuam nrog podocyte maturation, sib txawv, txheej txheem tsim, thiab signaling24. Peb qhov kev tshawb fawb pom tau tias muaj kev sib raug zoo ntawm kev txo qis ntawm nephrin qhia, raws li kev txiav txim los ntawm immunohistochemistry, thiab lub raum mob qib kev nce qib, qhia txog kev nthuav dav ntawm kev ua haujlwm ntawm cov txheej txheem podocyte ko taw. Txawm li cas los xij, nws tsis paub meej tias qhov txawv txav ntawm cov kab mob diaphragm protein complex ua rau kev puas tsuaj rau cov txheej txheem podocyte ko taw lossis yog tias qhov kev puas tsuaj ntawm podocyte ua rau muaj kev hloov pauv hauv slit diaphragms thiab nephrin txo. Txij li thaum nephrin tseem koom nrog hauv kev sib txawv ntawm podocyte, nws tau xav tias qhov kev sib raug zoo no yuav raug qhia ntxiv los ntawm cov ntaub ntawv ntawm podocyte regeneration thiab sib txawv.

Hauv kev xaus, peb cov txiaj ntsig muab cov ntaub ntawv ntawmnephrin uaKev nthuav qhia hauv kev loj hlob glomerulonephropathy hauv cov marmosets. Kev txheeb xyuas morphological tau qhia txog qhov qis dua ntawmnephrin uaKev qhia hauv podocytes hauv kev loj hlob glomerulonephropathy ntawm cov marmosets, thiab kev hloov pauv ntawmnephrin uaqhia tau hais tias ua lub luag haujlwm tseem ceeb hauv kev loj hlob ntawm lub raum lesions.

Kev nthuav tawm ntawm Muaj Peev Xwm Tsis Txaus Siab ntawm Kev Txaus Siab:

Cov kws sau ntawv tshaj tawm tias lawv tsis muaj kev tsis sib haum xeeb.

Kev lees paub:

Cov kws sau ntawv xav ua tsaug rau Mr. Takayoshi Ito rau qhov kev pabcuam zoo tshaj plaws uas lawv tau muab. Cov kws sau ntawv kuj ua tsaug rau Ms. Kanae Tamatsukuri thiab Mr. James Harada rau kev kho lus ntawm cov ntawv sau.

sib

Cov ntaub ntawv
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