Protease-Activated Receptor 1 Pab txhawb rau Microcirculation Failure Thiab Tubular puas nyob rau hauv lub raum Ischemia-Reperfusion Injury hauv nas.

Yug Guan,¹Daisuke Nakano,²Li Li,³Haofeng Zheng,³Akira Nishiyama,²Ye Tian,¹thiab Lei Zhang¹

los daws qhov ua tsis tiav nrogcistanche tshuaj ntsuab

1. Taw qhia

Covraumtsis tuaj yeem zam ischemia-reperfusion (IR) raug mob thaum lub sij hawm ib feem ntawm nephrectomy thiabraumkev hloov pauv [1], uas paub tias ua rau khaws cia cov khoom pov tseg hauv cov khoom lag luam metabolic thiab ua rau mob hnyav.raumraug mob (AKI) thiabAKI- mob ntevraumkab mob (AKI-CKD) [2]. Txog rau tam sim no, tsis muaj kev kho tshuaj tshwj xeeb tau kho rau AKI thiab AKI-CKD [3]. Ntau qhov kev hloov pauv pathological tshwm sim hauv AKI, xws li microcirculation tsis ua haujlwm [4], suav nrog kev mob plab thiab hemorrhage, thiab mob tubular necrosis [5]. Yog li ntawd, cov kev tshawb fawb tau tsom mus rau lub hom phiaj ntawm cov kev hloov pauv pathological no raws li cov kws kho mob muaj peev xwm. Peb yav tas los qhia tau hais tias tswj cov peritubular capillaries tom qablub raumIR raug mob txo capillary congestion thiab ameliorated AKI rau CKD hloov [6]. Mob tubular necrosis tej zaum yuav nyuaj rau kho; Yog li, kev rov tsim dua tshiab ntawm tubules los ntawm tubular cell proliferation tej zaum yuav yog ib qho tseem ceeb rau kev tiv thaiv kom tsis txhob muaj lub raum ua haujlwm ntxiv [7].

Protease-activated receptor-1 (PAR-1) belongs rau tsev neeg protease-activated receptor (PAR) thiab paub tias yuav txhawb nqa los ntawm thrombin los ua kom platelet coagulation. Peb tsis ntev los no tau pom tias PAR-1 tau pab txhawb rau kev txhim kho ntawm kev raug mob glomerular raug mob [8]. Tsis tas li ntawd, thrombin/PAR-1 tau tshaj tawm los ua lub luag haujlwm hauv epithelial cell proliferation thiab apoptosis. Raws li cov yam ntxwv no, peb xav tias PAR-1 tau nrawm AKI qhov hnyav los ntawm kev tswj cov ntshav capillary coagulation lossis tubular regeneration. Hauv txoj kev tshawb no, peb tau tshuaj xyuas lub luag haujlwm ntawm PAR-1 los ntawm kev siv Q-94, PAR-1- xaiv tsis zoo allosteric modulator, hauv naslub raumIR raug mob qauv thiab thrombin-stimulated cultured tib neeg tubular hlwb.

Hu rau:joanna.jia@wecistanche.com

2. Cov ntaub ntawv thiab cov txheej txheem

2.1. Mob raum IR Mouse Model.

Txhua qhov kev sim tsiaj tau ua raws li Lub Tsev Haujlwm Saib Xyuas Tsiaj Tsiaj thiab Siv Pawg Kev sim cov lus qhia ntawm Capital Medical University. CovraumIR nas qauv tau tsim raws li tau piav qhia yav dhau los [8]. Luv luv, 8-cov nas muaj hnub nyoog C57/BL6 txiv neej tau txhaj tshuaj loog los ntawm kev txhaj tshuaj pentobarbital sodium (50 mg/kg; ip) thiab muab faib ua pawg hauv qab no: sham, I/R plus tsheb, thiab I/R (tsheb: saline 10 mg/kg iv) plus Q94 (a PAR-1 antagonist ntawm 10 mg/kg iv) pawg (n=7–8 hauv txhua pab). Rau lub raum sov IR raug mob raws tu qauv, cov nas tau txais uninephrectomy los ntsuas qhov kev puas tsuaj rau lub raum ua haujlwm; Tom qab ib lub lim tiam, lub raum pedicle tau clamped nrog kev puas tsuaj-dawb vascular clips rau 30 feeb. Tom qab reperfusion rau 48 h, nas tau txi; lawv lub raum cov ntaub so ntswg kuaj tau sau thiab kho nyob rau hauv 4 feem pua ​​paraformaldehyde tov los npaj paraffin blocks. Plasma tau txais los ntsuas ntshav urea nitrogen (BUN) thiab creatinine.

2.2. Khoom siv.

Q94 tau yuav los ntawm Tocris Bioscience (Bristol, UK). Lwm cov tshuaj tau txais los ntawm Sigma Aldrich (St. Louis, MO, USA) tshwj tsis yog hais tias lwm yam.

2.3. Kev ntsuam xyuas rau Creatinine thiab BUN.

Cov khoom siv tshuaj ntsuam xyuas lag luam (Creatinine Assay Kit ab65340; Abcam, Cambridge, UK) tau siv los ntsuas creatinine. Cov khoom siv tshuaj ntsuam BUN tau yuav los ntawm ABSBio™ (UREA NITROGEN Kit, CNHAO BIO, Beijing, Suav).

2.4. Histology.

Ua ntej embedding nyob rau hauv paraffin, lub raum cov ntaub so ntswg tau kho nrog 4 feem pua ​​paraformaldehyde. Lub raum paraffin blocks raug txiav rau hauv 2 μm ntu thiab mounted rau slides thaum hmo ntuj ntawm 25 degree C. Tom qab deparaffinization, cov seem tau stained nrog hematoxylin thiab eosin (H&E). Cov duab tau txais los ntawm kev siv lub microscope (BX-51}/DP-72; Olympus, Tokyo, Nyiv). Raws li yav dhau los tau piav qhia [9], lub raum-tubule kev puas tsuaj tau kuaj pom los ntawm ntau qhov kev hloov pauv hauv histopathological, xws li tubular dilation, congestion / hemorrhage, txhuam ciam teb poob, tubular cast formation, thiab cell lysis nrog sloughed khib nyiab hauv tubular lumen. Tubular puas tau qhab nia raws li feem pua ​​​​ntawm cov tubules puas: 0, tsis muaj kev puas tsuaj; 1,<25%; 2,="" 25–50%;="" 3,="" 51–75%;="" and="" 4,="">75 feem pua. Cov qhab nia tau ua nyob rau hauv qhov muag tsis pom.

2.5. Immunofluorescence thiab Immunohistochemistry.

Cov ntu tau npaj raws li tau piav qhia rau kev soj ntsuam histology (H&E) thiab tom qab ntawd incubated nrog 0.3 feem pua ​​hydrogen peroxide rau 30 feeb los thaiv cov endogenous peroxidases tom qab deparaffinization nrog xylene. Rau antigen retrieval, cov seem tau incubated nrog proteinase K (DAKO Cytomation, Glostrup, Denmark) rau 10 feeb. Tom qab thaiv nrog 10 feem pua ​​​​tshis cov ntshav, cov seem tau tsim nrog thawj cov tshuaj tiv thaiv ib hmos ntawm 4 degree C (anti-Kim 1 antibody, ab47635, Abcam; anti Ki67 antibody, ab15580, Abcam; anti-PAR-1 antibody, ab32611 , Abcam). Tom qab incubation nrog thawj cov tshuaj tiv thaiv, cov seem tau incubated nrog cov tshuaj tiv thaiv theem nrab ntawm 25 ° C rau 1 h. DAB substrate (DAKO) tau siv los ua kom pom cov txiaj ntsig ntawm immunohistochemistry (IHC) staining. Cov teeb liab fluorescence tau kuaj pom siv Alexa Fluor 594-labeled thib ob antibody. Cov duab raug ntes siv FL fluorescence microscope (BX51; Olympus) nrog lub lim tsim nyog. ImageJ software (NIH, Bethesda, MD, USA) tau siv los txheeb xyuas qhov zoo.

2.6. Real-Time PCR.

Txhawm rau ntsuas qhov kev tswj hwm ntawm mRNA qhia nyob rau hauv cov xwm txheej no, mRNA raug cais tawm ntawm lub raum cov ntaub so ntswg. PCR System (7300 Fast Real-Time; Applied Biosystems, Foster City, CA, USA) thiab Light Cycler Fast Start DNA Master SYBR Green I cov khoom siv (Applied Biosystems) tau siv los txheeb xyuas cov qib 18S thiab PAR-1 mRNA. Primer sequences tau raws li nram no: 18S —5′ -GTAACCCGTTGAACCCCATT-3′, 5′-CCATCCAATCG GTAGTAGCG-3′; PAR-1—5′-GTTGATCGTTTCCACG GTCT-3′, 5′-GCTGCCTTGTTACCAGGACT-3′. Tus txheeb ze mRNA qib tau txiav txim siab siv txoj kev 2−ΔΔCq. Tus nqi ΔΔCq tau suav nrog cov ntaub ntawv los ntawm pawg tswj hwm.

2.7. Cov txheej txheem phais thiab hauv Vivo Multiphoton Imaging Settings.

Cov nas tsuag tau tshuaj loog nrog 2 feem pua ​​​​ isofurane (Mylan, Osaka, Nyiv). Tom qab tracheotomy, cov hlab ntsha jugular tau cannulated rau kev txhaj tshuaj fluorescent dye thiab infusion ntawm kev saib xyuas cov kua, uas muaj 1.0μL / min ntawm 2 feem pua ​​​​ albumin hauv phosphate-buffered saline. Lub raum sab laug ntawm txhua tus nas raug sab nrauv los ntawm ib qho me me flank incision thiab txuas rau daim npog. Lub tshuab kuaj kab mob theem thiab cov tsiaj tau ua kom sov siv lub tshuab cua sov thaum txhua qhov kev sim. Intravital multiphoton microscopy tau ua tiav siv Olympus FV1000MPE multiphoton confocal fluorescence imaging system powered los ntawm Chameleon Ultra-II MP laser ntawm 860nm (Coherent, Inc., Santa Clara, CA, USA). Lub hom phiaj microscope yog 25x dej immersion lens nrog 1.05 tus lej aperture. Cov kev teeb tsa duab rau lub tshuab tsom iav (tau txais thiab ua haujlwm rau tag nrho peb txoj kab; xiav, ntsuab, thiab liab) tau kho thoob plaws qhov kev sim. Tom qab 30min lub sijhawm rov qab los, rhodamine B- 70kD dextran tau txhaj rau hauv cov hlab ntsha, thiab 3-D z-pawg cov duab raug coj mus rau qhov tob ntawm 5-50 μm (2μm sib nrug) ntawm lub raum.

2.8. Cell Culture.

Tib neeg lub raum 2 (HK2) hlwb tau txais los ntawm Cell Bank of Academy Sciences (Shanghai, Tuam Tshoj) thiab kab lis kev cai raws li tau piav qhia yav dhau los [10]. Cov hlwb raug coj mus rau hauv Dulbecco's modified Eagle nruab nrab ntxiv nrog 10 feem pua ​​​​fetal bovine serum thiab 1 feem pua ​​penicillin-streptomycin nyob rau hauv ib qho chaw humidified ntawm 95 feem pua ​​​​ntawm huab cua thiab 5 feem pua ​​CO2 ntawm 37 degree.

2.9. WST-1 Kev soj ntsuam los soj ntsuam Cell Proliferation.

HK2 hlwb tau cog rau hauv 6- cov phiaj zoo ntawm qhov ntom ntawm 1 × 104 hlwb/- zoo. Tom qab stimulating HK2 hlwb nrog thrombin, WST - 1 kev soj ntsuam tau ua raws li cov chaw tsim khoom raws tu qauv (catalog #C0035; Beyotime, Shanghai, Suav teb) los txiav txim siab proliferative muaj peev xwm ntawm hlwb. Tom qab 2h ntawm incubation nrog 100μL WST -1 reagent nyob rau hauv txhua lub qhov dej, qhov nqus ntawm cov qauv raug ntsuas los ntawm kev nyeem ntawv microplate ntawm lub wavelength ntawm 450nm.

2.10. Caspase-3 Assay.

Caspase-3 kev ua haujlwm tau ntsuas los ntawm kev siv cov khoom siv caspase{1}} (catalog #C1116; Beyotime, Shanghai, Suav teb) [11]. Tom qab incubation nrog cov caspase-3 cov khoom siv reagent, qhov nqus ntawm cov qauv tau kuaj pom siv lub microplate nyeem ntawv (Spectra- Max M2, Molecular Devices, Sunnyvale, CA, USA) ntawm 405nm raws li cov chaw tsim khoom cov lus qhia.

2.11. Cov ntaub ntawv thiab Kev Tshawb Fawb Txog Kev Tshawb Fawb.

Ib txoj kev tsom xam ntawm qhov sib txawv tau siv los sib piv ntau pawg, ua raws li Tukey qhov kev sib piv ntau yam. Txhawm rau sib piv ob pawg neeg, peb siv Student's t-test. p < 0:05="" tau="" txiav="" txim="" siab="" los="" qhia="" txog="" cov="" txiaj="" ntsig="" tseem="">

Cistanche tubulosativ thaiv kab mob raum

3. Cov txiaj ntsig

3.1. PAR-1 Kev nthuav qhia hauv IR raum.

Peb thawj zaug tau lees paub qhov kev qhia ntawm PAR-1 thiab qhov cuam tshuam ntawm IR ntawm nws cov theem qhia hauv qhovraum. Peb tau pom ze li ntawm 2-fold nce qib ntawm kev qhia ntawm PAR-1 mRNA piv rau qhov ntawd hauv kev phais nas ntawm 48 h (Daim duab 1(a)). Peb kuj tau ntsuas qhov qhia ntawm PAR-1 los ntawm immunofluorescence ntawm 48 teev tom qab IR. PAR-1 tau qhia nyob rau hauv tubular cell txhuam ciam teb membrane. Qib ntawm PAR-1 FL fluorescence tau kho dua piv rau sham pawg nas (Daim duab 1(b) thiab 1(c)). Cov ntaub ntawv no qhia tias ob qho tib si hauv cheeb tsam ntawm PAR-1 hauv tubular hlwb thiab nws cov theem qhia tau raug kho tom qab IR hauv lub raum.

3.2. Lub raum Function thiab Histopathological Alterations. Peb ntsuasraumNws ua haujlwm los ntawm kev txheeb xyuas cov qib BUN thiab creatinine hauv cov ntshav. I / R induced nce qib ntawm BUN thiab creatinine piv rau cov nas uas raug phais sham. Ntxiv mus, IR-induced nce qib BUN tau txo qis hauv Q94-cov nas kho (Daim duab 2(a)). Cov qib creatinine hauv cov ntshav tau inhibited hauv Q94- kho cov nas piv rau cov nas tsuas yog raug IR phais (Daim duab 2(b)). Cov ntaub ntawv no qhia tias kev tswj hwm ntawm Q94 tuaj yeem tiv thaivraumua haujlwm tom qab IR raug mob.

Peb kuj tau soj ntsuam cov kev hloov hauv lub raum histopathological los ntawm kev ua H&E staining. Lub raum IR ua rau muaj zog ntau ntxiv, tubular dilatation, thiab txhuam ciam teb poob thiab congestion / hemorrhage nyob rau hauv lub tsheb-kho nas piv rau sham nas. Q94 kev kho mob tau txo qis cov kev hloov pauv no los ntawm IR (Daim duab 2(c) thiab 3(a)). Kev soj ntsuam ntawm H&E staining cov txiaj ntsig ntawm cov pab pawg tau nthuav tawm cov qhab nia / cov ntshav ntshav thiab cov qhab nia tubular puas tsuaj rau txhua pab pawg. Q94 pab pawg nas pom qhov qhab nia qis dua (Daim duab 2(e) thiab 3(c)). Peb kuj stain Kim-1 ua ibraumKev raug mob ntawm lub raum tubular hlwb los ntawm IHC [12]. Kim-1- thaj chaw zoo tau nce hauv lub raum tubular cheeb tsam hauv cov nas nrog IR kev thuam, uas tau cuam tshuam loj heev los ntawm Q94 (Daim duab 2(d) thiab 2(f)). Cov ntaub ntawv no qhia tias Q94 tuaj yeem cuam tshuamraumtubular puas induced los ntawm IR raug mob.

3.3. Ntshav Cell Flow nyob rau hauv Vivo Imaging.

PAR-1 thiab nws cov ligand thrombin ua lub luag haujlwm tseem ceeb hauv kev sib tsoo; Q94 ua rau muaj kev sib kis tau zoo. Yog li ntawd, peb tau ua intravital imaging los ntawm multiphoton microscopy. Qhov no ua rau kev soj ntsuam ntawm cov ntshav hauv cov ntshav hauv peritubular capillary hauv lub sijhawm tiag tiag hauv cov nas nyob (Daim duab 3(c)). Plasma tau pom los ntawm 70 kDa dextran conjugated nrog rhodamine B (Daim duab 3(d)). Cov qe ntshav uas tsis tsim FL fluorescence nyob rau hauv cov lus teb rau lub laser tau siv los excite rhodamine B thiab piav raws li duab ntxoov ntxoo. Raws li pom nyob rau hauv daim duab 3(e), lub raum IR cuam tshuam cov ntshav cell raws li niaj zaus thiab induced microcirculation tsis ua hauj lwm. Q94 txhim kho peritubular capillary cov ntshav cell khub.

3.4. Tubular Cell Proliferation tom qab IR raug mob.

Nws tau raug tshaj tawm tias qhov kev loj hlob ntawm cov tubular hlwb plays lub luag haujlwm tseem ceeb hauv kev kho cov qauv tubular thiab lub raum ua haujlwm tom qab IR raug mob. PAR-1 paub tias yuav hloov pauv qhov loj hlob ntawm cov hlwb epithelial thaum qhib los ntawm thrombin. Yog li peb tau kuaj pom qhov kev loj hlob ntawm lub raum tubular hlwb hauv Ki-67 IHC kev soj ntsuam. Thaum 48 teev tom qab IR, tus naj npawb ntawm proliferating Ki-67- zoo tubular hlwb tau nce. Q94 ntxiv qhov nce ntxiv ntawm Ki-67- cov cell tubular zoo tom qab IR piv rau cov nas uas kho IR nkaus xwb (Figures 4(a) thiab 4(b)). Tsis tas li ntawd, peb tau kuaj xyuas seb lub cell proliferation muaj peev xwm cuam tshuam los ntawm inhibition ntawm PAR-1 nyob rau hauv vitro thwmsim siv HK2 hlwb incubated nrog thrombin, ib tug PAR-1 agonist. Kev ua haujlwm loj ntawm HK2 hlwb tau ntsuas los ntawm WST-1 kev soj ntsuam. Raws li pom nyob rau hauv daim duab 4(c), kev loj hlob ntawm HK2 hlwb raug txo qis tom qab kev kho mob nrog thrombin. Txawm li cas los xij, qhov inhibition thrombin-induced yuav luag raug tshem tawm los ntawm Q94. Cov ntaub ntawv no qhia tias PAR-1 tsis zoo tswj kev loj hlob ntawm lub raum tubular hlwb, uas yuav luag tshem tawm los ntawm Q94 PAR-1 antagonist.

kom txo tau tus kab mob raum mob nrogcistanche

3.5. Lub raum Tubular Cell Apoptosis.

Peb tau soj ntsuam ntxiv rau apoptosis ntawm lub raum hlwb siv caspase-3, uas yog qhov tseem ceeb tshaj plaws executioner caspase thiab tau qhib los ntawm ob qho tib si sab hauv thiab sab hauv txoj hauv kev thaum lub sij hawm apoptosis [13]. Siv thrombin-incubated kab lis kev cai HK2 hlwb, peb pom tias thrombin nce kev ua haujlwm ntawm caspase-3. Ntxiv mus, kev tswj hwm ntawm Q94 tau txwv tsis pub ua haujlwm ntawm caspase-3 (Daim duab 4(d)). Cov ntaub ntawv no qhia tias thrombin-induced apoptosis ntawm HK2 hlwb tau inhibited los ntawm Q94 PAR-1 antagonist.

4. Kev sib tham

Lub raumKev raug mob IR yog yam ntxwv los ntawm congestion / hemorrhage, mob tubular necrosis, o, thiab deposition ntawm cast formation [5]. Ntawm no, peb tau pom tias inhibition ntawm PAR-1 ameliorated ob leeg ntshav sib koom nrog kev hloov pauv thiab tubulointerstitial hloov pauv. Nws paub zoo tias PAR-1 thiab nws cov ligand, thrombin, ua lub luag haujlwm tseem ceeb hauv platelet coagulation, thiab cuam tshuam ntawm cov kab ke no, xws li los ntawm thrombomodulin [14, 15], tuaj yeem tiv thaiv AKI. Peb tau pom tias PAR- 1 inhibition suppressed congestion thiab txhim kho cov ntshav khiav hauv peritubular capillaries hauv nas nrog raum IR raug mob, qhia tias PAR-1 system deteriorated microcirculation. Tsis tas li ntawd, qib kev qhia ntawm PAR-1 tau raug kho hauv cov tubules tom qab lub raum IR raug mob, qhia tias PAR-1-nyob rau hauv cov tubules kuj exaggerates raum IR raug mob. Nws yog qhov tsim nyog tias kev tsim kho ntawm cov tubular hlwb yog cov txheej txheem tseem ceeb hauv kev tsim kho cov qauv tubular thiab rov ua kom lub raum ua haujlwm tom qab IR raug mob [16, 17]. Nyob ntawm qhov kev raug mob, qhov kev kho lub peev xwm no tsis txwv [18]. Yog li ntawd, txoj kev kho mob kom txo qis kev puas tsuaj hauv tubular hlwb los yog ua kom lawv cov kev loj hlob sai yog qhov xav tau sai. Peb txoj kev tshawb fawb hauv vitro tau pom tias PAR- 1/thrombin tsis zoo tswj kev loj hlob ntawm tubular hlwb, uas tau ua kom nrawm dua tom qab inhibition ntawm PAR-1. Tsis tas li ntawd, IR raug mob hauv cov nas tau pom tias yuav ua rau cov tubular proliferation ntawm 48 h, nrog kev nce ntxiv tom qab PAR-1 inhibition. Peb pom tias PAR-1 tau nce nyob rau hauv txhuam ciam teb ntawm cov tubules ze ze. Raws li nws tau tshaj tawm tias kev ua haujlwm ntawm glomerular filtration barrier txo qis thaum lub raum IR raug mob [19], lim thrombin los ntawm glomeruli tuaj yeem ua kom muaj zog PAR - 1, yog li cuam tshuam cov tubular regeneration.

Peb cov txiaj ntsig tau qhia tias PAR-1/thrombin system txwv kev loj hlob ntawm tubular hlwb thiab nce apoptosis. Txawm li cas los xij, lwm txoj kev tshawb fawb tau pom qhov cuam tshuam ntawm PAR-1 thaum qhib los ntawm cov protein C [20, 21]. Lub luag haujlwm tsis sib haum xeeb ntawm PAR-1 no tuaj yeem nyob ntawm txoj kev ua kom nws ua. Hauv peb txoj kev tshawb fawb, qhov kev piav qhia ua tau rau nws lub luag haujlwm yog tias PAR-1 tau qhib los ntawm lim thrombin. Qhov loj ntawm cov protein C yog tshaj 60 kDa, uas zoo ib yam li cov albumin [22, 23] thiab loj dua li ntawm thrombin (36 kDa). Tsis tas li ntawd, nws cov plasma concentration (<100 nm)="" is="" less="" than="" 10%="" of="" thrombin="" (="">1 μM), qhia tau hais tias cov protein C tau pom tsawg dua thiab tsim cov teeb liab tsis muaj zog piv rau thrombin.

Thrombotic ntu yog qhov muaj feem pheej hmoo rau cov neeg mob uas lub raum tsis ua haujlwm kawg [24]. Ib txoj kev tshawb nrhiav pom tias PAR-1 tsis muaj peev xwm tiv thaiv tus mob ntshav qab zib CKD [25]. Hauv peb txoj kev tshawb fawb, peb tau pom cov txiaj ntsig ntawm inhibition ntawm PAR-1 ntawm lub raum kev ua haujlwm ntawm theem pib tom qab IR. Hauv kev tshawb fawb ntxiv, peb npaj siab yuav txhim kho tus mobraumIR-induced kab mob qauv [2] los ntsuas qhov muaj peev xwm txuas ntawm PAR-1 nrog CKD.

Hauv kev xaus, peb tau pom tias PAR-1 ua rau cov microcirculation tsis ua haujlwm thiab ua rau tsis zoo rau kev loj hlob ntawm tubular hlwb. Piv txwv li, inhibition ntawm PAR-1 pab txhawb kev txhim kho microcirculation thiab proliferation ntawm tubular hlwb thiab tom qab IR, ua hauj lwm raws li ib tug tseem ceeb mechanism ntawm lub raum rov qab, thiab yuav tsum tau xav txog ib tug tshiab lub tswv yim nyob rau hauv kev kho mob ntawm AKI.

Cistanche tubulosa tiv thaiv kab mob raum, nyem qhov no kom tau txais cov qauv

1 Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing, Suav

2 Department of Pharmacology, Kagawa University, Kagawa, Nyiv

3Division of Kidney Transplantation, Department of Surgery, The Third Affiliated Hospital of Sun Yat-sen University,

Guangzhou, Suav teb

Cov ntawv xov xwm yuav tsum tau hais rau Ye Tian; kidney@ccmu.edu.cn thiab Lei Zhang; leizhangkidney@gmail.com Tau txais 1 Lub Ib Hlis 2021; Hloov kho 25 Lub Ib Hlis 2021; Tau txais 8 Lub Ob Hlis 2021; Luam tawm Lub Ob Hlis 23, 2021

Academic Editor: Junyan Liu

Copyright © 2021 Yu Guan et al. Qhov no yog ib tsab xov xwm qhib-access faib nyob rau hauv lubCreative Commons Attribution License, uas tso cai rau kev siv tsis txwv, kev faib tawm, thiab luam tawm hauv ib qho nruab nrab, yog tias cov haujlwm qub raug suav hais tias yog.

Ischemia-reperfusion- (IR-) cuam tshuam rau lub raum raug mob yog qhov nyuaj kom tsis txhob muaj lub raum hloov pauv thiab cov neeg hlau pab ib nrab nephrectomy. Lub raum IR raug mob yog tus yam ntxwv ntawm tubular puas, microcirculation tsis ua hauj lwm, thiab o, uas ua rau lub raum raug mob; Txawm li cas los xij, tsis muaj kev kho mob tshwj xeeb rau cov mob no. Protease-activated receptor-1 (PAR-1) thiab nws cov ligand, thrombin, koom nrog hauv coagulation thiab tau pom tias muaj feem cuam tshuam nrog kev raug mob ntawm tes epithelial. Ntawm no, peb xav tias PAR-1 exaggerated lub raum IR-induced tubular cell puas thiab microcirculation tsis ua hauj lwm thiab cov pharmacological inhibition ntawm PAR-1 los ntawm Q94 tuaj yeem tiv thaiv cov kev raug mob no. Lub raum sov IR nce qhov kev qhia ntawm PAR-1 hauv lub raum tubules. Q94 attenuated raum IR-induced hloov pauv thiab histopathological puas. Microcirculation tsis ua hauj lwm tau soj ntsuam los ntawm congestion nyob rau hauv lub histopathology thiab cov ntshav cell flow soj ntsuam los ntawm intravital multiphoton microscopy twb suppressed los ntawm Q94 kev kho mob. Q94 kuj tseem ua rau muaj kev loj hlob ntawm tubular cell proliferation txawm tias lub raum tsis zoo. Thrombin suppressed cell proliferation thiab induced apoptosis hauv tubules; Cov kev cuam tshuam no tau tiv thaiv los ntawm kev kho Q94. Ua ke, PAR-1 tau cuam tshuam nrog rau lub raum IR raug mob. Inhibition of PAR-1 ameliorated raug mob tej zaum los ntawm kev txhim kho lub raum microcirculation thiab tubular cell ciaj sia taus / proliferation.

Data Availabua ility

Cov kws sau ntawv lees paub tias cov ntaub ntawv txhawb nqa kev tshawb pom ntawm qhov kev tshawb fawb no muaj nyob hauv kab lus.

Cntawmflicts of Interest

Txhua tus kws sau ntawv tau tshaj tawm tias lawv tsis muaj kev sib tw.

Authors' Cntawmtriua butintawms

Yu Guan thiab Daisuke Nakano tau sau cov ntawv sau thiab ua kev sim tsiaj. Lei Li ua qhov kev sim hauv vitro. Haofeng Zheng ua qhov kev txheeb xyuas kev txheeb xyuas. Akira Nishiyama tau hloov kho cov ntawv sau. Lei Zhang thiab Ye Tian tsim txoj kev tshawb no.

Acknowledgments

Txoj kev tshawb no tau txhawb nqa los ntawm National Natural Science Foundation ntawm Tuam Tshoj (No. 82000712) thiab Tuam Tshoj Postdoctoral Science Foundation (No. 2020M670385).

Cov ntaub ntawv

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