Coagulation, Protease-Activated Receptors, Thiab Mob raum Ntshav Qab Zib: Cov Lus Qhia Los Ntawm ENOS-Deficient nas
Feb 02, 2024
Endothelial nitric oxide synthase(eNOS) kev ua haujlwm tsis zoo yog paub tias yuav ua rau muaj kev loj hlob thiab kev cia siab ntawmmob ntshav qab zib raum(DKD). Ib qho ntawm cov txheej txheem los ntawm qhov no tau ua tiav yog tias qib eNOS qis yog txuam nrog hypercoagulability, uas txhawb kev raug mob raum. Nyob rau hauv extrinsic coagulation cascade, cov ntaub so ntswg yam (factor III) thiab downstream coagulation yam, xws li active factor X (FXa), exacerbate o los ntawm activation ntawm protease-activated receptors (PARs). Tsis ntev los no, nws tau pom tias qhov tsis muaj lossis txo eNOS kev qhia hauv cov nas mob ntshav qab zib, raws li tus qauv ntawm DKD siab heev, nce raum cov ntaub so ntswg ntau ntau thiab PAR1 thiab 2 qhia hauv lawv lub raum. Tsis tas li ntawd, kev siv tshuaj inhibition lossis genetic deletion ntawm coagulation yam lossis PARsameliorated mobhauv DKD hauv nas tsis muaj eNOS. Hauv qhov kev tshuaj xyuas no, peb sau cov kev sib raug zoo ntawm eNOS, coagulation, thiab PARs thiab nthuav tawm cov kev xaiv kho tshiab rau kev tswj cov neeg mob nrog DKD.
Ntsiab lus:mob ntshav qab zib glomerulosclerosis; factor Xa;mob; cov ntaub so ntswg
Nyem qhov no kom tau txais Natural organic CISTANCHE EXTRACT nrog 25% ECHINACOSIDE thiab 9% ACTEOSIDE rau lub raum ua haujlwm
Taw qhia
Tus naj npawb ntawm cov neeg mob nrogmob ntshav qab zib raum(DKD) nce thoob ntiaj teb (de Boer li al. 2011; Kainz li al. 2015; Ogurtsova li al. 2017). DKD yog ib qho ntawm cov laj thawj tseem ceeb ntawm kev tuag hauv cov neeg mob uas muaj mob ntshav qab zib mellitus (Afkarian li al. 2013). Tsis tas li ntawd, DKD muaj kev vam meej thiab yog qhov ua rau muaj kab mob raum kawg uas yuav tsum tau kho lub raum (Gregg li al. 2014; Liyanage li al. 2015). Hauv Nyij Pooj, ntshav qab zib nephropathy suav txog ntau dua 39% ntawm cov neeg mob ntshav lim ntshav tshiab (Nitta li al. 2020). Yog li ntawd, txoj kev loj hlob ntawmkho tshiabCov kev xaiv yuav tsum tau tswj cov neeg mob nrog DKD.
system nyob rau hauv DKD pathogenesis. Hypercoagulability yog txuam nrog DKD (Goldberg 2009; Domingueti li al. 2016). Kev nce qib fibrinogen hauv cov ntshav tau pom tias muaj feem cuam tshuam nrog qis glomerular filtration rate, siab proteinuria, thiab mob histological raug mob hnyav, thiab nws yog ib qho kev kwv yees ntawm kev loj hlob mus rau theem kawg ntawm lub raum kab mob (Dalla Vestra li al. 2005; Pan et al. 2018; Zhang et al. 2018). Qee qhov kev tshawb fawb tau qhia txog kev sib raug zoo ntawm qib D-dimer, cov khoom lag luam fibrin degradation, thiab lub raum tsis ua haujlwm hauv DKD (Domingueti li al. 2018; Pan et al. 2018). Hypercoagulability hauv DKD yuav txiav txim siab los ntawm ntau yam. Piv txwv li, renin-angiotensin-aldosterone system activates cov ntaub so ntswg (TF, factor III) thiab ua rau cov txheej xwm thrombotic (Dielis li al. 2005). Txwv tsis pub, hyperglycemia, dyslipidemia, o, lossis endothelial dysfunction tau koom nrog hauv lub xeev pro-thrombotic raws li DKD pathogenesis (Goldberg 2009).
Endothelial dysfunction muaj nyob rau hauv DKD uas nce mus rau microvascular teeb meem (Goldberg 2009; Nakagawa li al. 2011). Impaired endothelial nitric oxide synthase (eNOS) ntau lawm lossis txo eNOS kev ua (piv txwv li, impaired eNOS phosphorylation) yog ib qho cim ntawm endothelial dysfunction hauv DKD (Nakagawa li al. 2011; Cheng et al. 2012). Peb tau pom tias qhov poob ntawm eNOS qhia tau txuas nrog qhov nce siab hauv qib TF thiab kev ua haujlwm ntawm cov kab mob extrinsic coagulation (Li et al. 2010; Wang et al. 2011a), uas cuam tshuam nrog cov xwm txheej thrombotic hauv cov neeg mob raum mob. kab mob (Kolachalama et al. 2018).
Ntxiv rau qhov kev pheej hmoo siab ntawm cov xwm txheej thrombotic, coagulation proteases, xws li active yam FVII (FVIIa), active factor (FXa), thiab thrombin, uas muaj nyob rau hauv lub extrinsic coagulation cascade, kho cov nqaij mos raug mob los ntawm ib tug protease-activated receptor ( PAR)-dependent mechanism (Madhusudhan li al. 2016; Posma et al. 2019). Hauv qhov kev tshuaj xyuas no, peb nthuav tawm cov kev tshawb pom tau los ntawm cov nas mob ntshav qab zib uas tsis muaj eNOS thiab sib tham txog kev sib raug zoo ntawm txoj kev coagulation-PAR, qib eNOS, thiabDKD kab mob.
Tissue Factor/Protease-Activated Receptors Pathway
Cov ntaub so ntswg (TF), lub npe hu ua factor III, yog 47 kDa transmembrane protein uas cuam tshuam nrog yam VII (FVII) (Grover thiab Mackman 2018). Lub TF / FVIIa complex yog ib qho activator ntawm extrinsic coagulation cascade thiab catalyzes lub activation ntawm FX thiab FIX. FXa thiab activated co-factor V (FVa) tsim ib txoj hauv kev prothrombotic uas tsim cov thrombin. Thaum kawg, thrombin hloov fibrinogen rau fibrin, uas ua rau tsim cov thrombi (Grover thiab Mackman 2018). TF yog qhia nyob rau hauv ob lub vascular du leeg hlwb thiab adventitial fibroblasts. Nyob rau hauv cov kab mob inflammatory, nws cov lus qhia yog induced nyob rau hauv endothelial hlwb los yog circulating hlwb xws li monocytes (Østerud thiab Bjørklid 2006).
Protease-activated receptors (PARs) yog cov tswv cuab ntawm G-protein-coupled receptor superfamily, suav nrog plaub PAR proteins (PAR1-4). PARs tau txais kev sib cais los ntawm cov proteases ntawm N-terminal kawg thiab tau qhib thaum khi rau N-terminus tshiab uas muaj cov tethered ligand. Plaub tus tswv cuab ntawm PARs (PAR1-4) yog qhib los ntawm cov coagulation proteases: TF thiab FVIIa complex activates PAR2, factor Xa activates PAR1 thiab PAR2, thiab thrombin activates PAR1, PAR3, thiab PAR4 (Camerer li al. 2000; Coughlin 2005; Rothmeier thiab Ruf 2012; Zhao et al. 2014). Kev sib raug zoo ntawm TF, coagulation proteases, thiab PARs yog qhia hauv daim duab 1.
PARs paub tias tau nthuav dav dav hauv lub raum hlwb thiab koom nrog hauv pathophysiology ntawm lub raum raug mob. Ob leeg PAR1 thiab PAR2 yog qhia nyob rau hauv glomerular endothelial hlwb, mesangial hlwb, thiab raum tubular hlwb muab tau los ntawm tib neeg los yog nas; PAR2, PAR3, thiab PAR4 yog qhia nyob rau hauv tib neeg podocytes; PAR1, PAR3, thiab PAR4 yog qhia hauv murine podocytes (Tanaka li al. 2005; Vesey li al. 2005; Madhusudhan li al. 2012; Dong et al. 2015; Madhusudhan et al. 2016).
Txawm hais tias muaj teeb meem los yog kev tiv thaiv los ntawm PARs hauvmob raumtau pom, accumulating cov ntaub ntawv qhia tias PARs exacerbate o los ntawm stimulating zus tau tej cov cytokines thiab chemokines (Rothmeier thiab Ruf 2012; Isermann 2017; Posma li al. 2019). Raws li qhov kev tshawb pom no, PAR1 thiab PAR2 agonists txhawb kev nthuav qhia ntawm cov kab mob sib kis, xws li monocyte chemotactic protein 1 (MCP1) thiab plasminogen activator inhibitor-1 (PAI-1), thiab pro-fibrotic molecules hauv endothelial. , mesangial, thiab raum tubular cells (Vesey et al. 2005; Vesey et al. 2013; Ellinghaus et al. 2016; Waasdorp et al. 2016; Oe et al. 2019). Hauv kev tshawb fawb vivo, qhov tsis muaj PAR1 lossis muaj PAR1 inhibitors txo qhov mob hauv cov qauv ntawm crescentic glomerulonephritis lossis obstructive raum raug mob (Cunningham li al. 2000; Waasdorp li al. 2019; Lok et al. 2020). Ib yam li ntawd, cov kev kho mob ntawm PAR2 inhibition nyob rau hauv lub raum raug mob tau nrog los ntawmtxo qhov mobhauv lub raum (Hayashi li al. 2016; Du et al. 2017; Han et al. 2019; Watanabe et al. 2019).
Endothelial Nitric Oxide Synthase Polymorphisms hauv DKD
Endothelial nitric oxide synthase(eNOS) yog ib qho ntawm peb NOS isoforms, thiab nws pab txhawb kev tsim NO hauv cov hlab ntsha endothelium (Walford thiab Loscalzo 2003). TSIS tsim los ntawm eNOS nyob rau hauv vascular endothelium plays lub luag haujlwm tseem ceeb hauv kev tswj hwm vascular so, tiv thaiv kab mob, thiab tiv thaiv kev tsim cov thrombus (Walford thiab Loscalzo 2003). Impaired eNOS qhia yog txuam nrog kev loj hlob ntawm DKD. Tsis ntev los no tau ua meta-kev tshuaj ntsuam xyuas ntawm tib neeg tau qhia tias G894T (rs1799983), C-786T (rs2070744), thiab intron 4b/4a (rs{10}}) hauv eNOS (NOS3) cov noob muaj feem cuam tshuam nrog kev loj hlob ntawm DKD (Dellamea et al. 2014; Zhang et al. 2015; Dong et al. 2018). Ntawm cov kev hloov pauv no, lub luag haujlwm ntawm G894T (Glu298Asp) polymorphism hauv eNOS muaj nuj nqi tau ua tau zoo. Qhov txo qis ntawm NO lossis nitrite tsub zuj zuj tau qhia hauv cov kab mob CHO cov hlwb nrog 298Asp piv rau cov uas muaj 298Glu (Noiri li al. 2002). Ua ke, cov txiaj ntsig no qhia tau tias qhov txo qis ntawm NO los ntawm eNOS ua haujlwm tsis zoo yog qhov tseem ceeb rau kev loj hlob ntawm DKD hauv tib neeg.
Cov nas mob ntshav qab zib tsis muaj eNOS ua tus qauv ntawm Tib neeg mob ntshav qab zib nephropathy
Kev tsim cov qauv kev kho mob txhim khu kev qha zoo ib yam li tib neeg DKD yog qhov tseem ceeb rau kev kawm txog cov kev kho tshiab tshiab. Raws li cov ntaub ntawv pov thawj qhia txog kev koom tes ntawm eNOS polymorphism thiab DKD, ntau cov kev tshawb fawb tau pom tias eNOS knock-out qauv ntawm hom I thiab hom II DM yog qee cov qauv ua tau zoo ua rau tib neeg DKD (Brosius et al. 2009; Azushima et al. 2018). Nws tau pom tias streptozotocin-induced ntshav qab zib nas tsis muaj eNOS tsim mob hnyav albuminuria, mesangial expansion, thickening ntawm glomerular qab daus daim nyias nyias, thiab arteriolar hyalinosis, zoo li tib neeg DKD (Nakagawa li al. 2007). Ib yam li ntawd, hom II mob ntshav qab zib nas (db / db) tsis muaj eNOS pom tias muaj mob glomerulosclerosis thiab albuminuria (Zhao li al. 2006).
Nce TF hauv Diabetic Mice Lacking eNOS
TSIS MUAJ inhibits thrombus tsim thiab platelet aggregation (Walford thiab Loscalzo 2003). Vim hais tias glomerular thrombus tsim tau pom nyob rau hauv cov nas mob ntshav qab zib tsis muaj eNOS (Nakagawa li al. 2007), qhov tsis zoo eNOS qhia yuav cuam tshuam nrog kev nce hauv TF-dependent coagulation. Kev koom tes ntawm eNOS thiab TF hauv DKD tau hais nyob rau hauv peb cov ntaub ntawv dhau los (Li et al. 2010; Wang et al. 2011a; Oe et al. 2016) (Fig. 2).
Kev txo qis lossis tsis muaj eNOS qhia ua kom lub raum TF kev ua si hauv cov neeg mob ntshav qab zib Akita nas Peb pom TF qhia hauv cov kab mob ntshav qab zib Akita (Ins2Akita / +) nas, tus qauv ntawm hom I DM, nrog ntau theem ntawm eNOS (eNOS +/+, eNOS+/- , and eNOS-/-) (Wang et al. 2011a). Peb pom tias qhov hnyav ntawm DKD cuam tshuam nrog txo eNOS qhia. Urinary albumin excretion, glomerulosclerosis, thiab txo cov glomerular pom tus nqi tau exacerbated raws li nram no: eNOS +/+; Ins2Akita/+
Kev noj zaub mov muaj roj ntau thiab tsis muaj eNOS synergistically nce TF hauv cov nas mob ntshav qab zib
Ntau qhov kev tshawb fawb tau pom tias muaj kev sib txuas ntawm kev rog thiab thrombosis (Samad thiab Ruf 2013). Piv txwv li, kev txhim kho ntawm TLR4-NF-kB txoj hauv kev nyob rau hauv cov kab mob metabolic nce qib TF (Lv li al. 2009; Owens li al. 2012; Rogero thiab Calder 2018). Tsis tas li ntawd, saturated fatty acid palmitate induces histone H3 tso tawm ntawm ROS thiab JNK txoj kev-nyob rau hauv cov txheej txheem thiab extracellular histones, uas nce TF qhia hauv monocytes (Shrestha li al. 2013). Kev tsom mus rau kev sib raug zoo ntawm coagulation, eNOS, thiab dyslipidemia, peb txoj kev tshawb fawb yav dhau los tau qhia txog kev sib xyaw ua ke ntawm eNOS tsis txaus thiab kev noj zaub mov muaj roj ntau ntawm TF qhia (Li et al. 2010). Hauv txoj kev tshawb no, eNOS-null nas tau kho nrog koob tshuaj STZ tsawg los tsim DM thiab tau noj cov zaub mov muaj roj ntau. Qhov tsis muaj eNOS qhia tau nce urinary albumin excretion thiab histological raug mob, uas tau ntxiv exacerbated los ntawm kev noj zaub mov muaj roj ntau. Kev qhia thiab kev ua ntawm TF tau nce hauv nas raum vim tias tsis muaj eNOS qhia thiab noj zaub mov muaj roj ntau hauv kev sib koom ua ke. Interestingly, nce qib ntawm immunoreactive TF tau pom los ntawm kev sim colocalization nrog glomerular monocyte / macrophage marker.
Neutralizing Antibodies tiv thaiv TF Ameliorate Inflammation hauv Diabetic raum hauv eNOS-Knockout nas
Kev nce hauv TF-dependent coagulation yog txuam nrog nce o (Witkowski li al. 2016). Inhibition ntawm TF-dependent coagulation system amelioratedkab mob inflammatory, xws li LPS-induced sepsis (Pawlinski li al. 2010). Txhawm rau nthuav tawm qhov kev sib txuas ntawm qhov mob thiab TF hauv DKD, peb tau tshuaj xyuas lub sijhawm luv luv ntawm cov tshuaj tiv thaiv kab mob tiv thaiv TF ntawm o ntawm lub raum mob ntshav qab zib hauv eNOS-tsis muaj nas (Li li al. 2010). Cov txiaj ntsig tau pom tias kev tswj hwm cov tshuaj tiv thaiv TF cov tshuaj tiv thaiv tau txo qis hauv lub raum qhia theem ntawm o- thiab fibrosis ntsig txog cov noob xws li Tnfa, Ccl2, Tgfb, thiab Col4 mRNA hauv nas raum plaub hnub tom qab TF neutralization.
Coagulation FXa Inhibitor Ameliorates raum Injury nyob rau hauv Diabetic Mice Lacking eNOS
Coagulation FXa, nyob hauv qab ntawm TF / VIIa, kuj tseem ua rau muaj mob los ntawm PAR-dependent txoj kev. Nws lub luag haujlwm hauv DKD tau pom nyob hauv ntau tus qauv tsiaj. Sumi et al. (2011) pom tau hais tias fondaparinux, FXa inhibitor, txo cov zis protein ntau, glomerular hypertrophy, thiab fibrin deposition hauv db/db nas. Cov nyhuv kho ntawm FXa inhibition hauv DKD nas tsis muaj eNOS tau pom los ntawm peb pawg (Oe li al. 2016). Edoxaban (50 mg / kg / hnub), ib qho tshuaj FXa inhibitor, tau muab rau eNOS-/-; Ins2Akita/+ nas rau peb lub hlis, thiab cov txiaj ntsig tau pom tias muaj kev raug mob histological, xws li mesangial matrix proliferation. Cov kev qhia theem ntawm cov kab mob inflammatory hauv lub raum raug txo los ntawm edoxaban (Table 1). FXa qhib ob qho tib si PAR1 thiab PAR2. Txhawm rau nthuav tawm cov txheej txheem ntawm FXa-mediated raum raug mob, peb tau pom tias cov tshuaj tiv thaiv kab mob ntawm FXa inhibitors zoo ib yam li cov pom hauv PAR2-/- nas thiab PAR2-/- nas nrog FXa inhibitors . Cov kev tshawb pom no tau qhia tias FXa yuav ua rau mob los ntawm PAR2-txoj kev nyob ntawm DKD. Hauv qhov sib piv, edoxaban tsis txhim kho glomerular raug mob hauv eNOS +/+; Ins2Akita/+ nas, qhia tias qhov kev kho mob ntawm FXa inhibition yog txuam nrog eNOS-dependent hypercoagulability nyob rau hauv hom I ntshav qab zib nas.
Lwm yam Coagulation Factors hauv DKD
Vim tias thrombin lub hom phiaj PAR1, uas ua rau mob vascular o (Chen thiab Dorling 2009), thrombin yuav ua rau DKD ntau dua. Txawm li cas los xij, txoj haujlwm tiv thaiv lossis teeb meem ntawm thrombin hauv DKD pathogenesis tau tshwm sim; Cov tshuaj thrombin qis (50 pM) tiv thaiv, thaum cov koob tshuaj thrombin siab (20 nM) ua rau hnyav zuj zus, cov piam thaj-induced apoptosis hauv podocytes (Wang et al. 2011b). Cov teebmeem ntawm thrombin inhibitors xws li dabigatran ntawm cov nas mob ntshav qab zib tsis muaj eNOS yuav tsum tau piav qhia yav tom ntej.
Fibrinogen koom nrog hauv ntau yam kev mob tshwm sim. Interestingly, ib feem txo qis lossis tsis muaj fibrinogen yog qhov zoo rau lub raum ischemia-reperfusion qauv lossis obstructive raum fibrosis (Sörensen li al. 2011; Craciun li al. 2014). Vim hais tias glomerular fibrin deposition yog nce nyob rau hauv cov nas mob ntshav qab zib tsis muaj eNOS (Nakagawa li al. 2007; Li et al. 2010; Wang et al. 2011a), elucidating nws lub luag hauj lwm hauv DKD pathogenesis tsim nyog tshawb fawb ntxiv.
Kev nthuav qhia ntawm PAR1 thiab PAR2 hauv cov nas mob ntshav qab zib tsis muaj eNOS
Kev nthuav qhia ntau ntxiv ntawm PARs cuam tshuam nrog rau lub raum raug mob. Peb thiab lwm tus tau pom tias cov theem ntawm Par1 thiab / lossis Par2 mRNA tau nce hauv cov qauv tsiaj nrog mob ntshav qab zib nephropathy, ade cuaj-induced raum raug mob, obstructive raum fibrosis, thiab cisplatin-induced raum raug mob (Chung et al. 2013; Hayashi thiab al. 2016; Oe et al. 2016; Watanabe et al. 2019). Tsis tas li ntawd, glomerular PAR2 cov protein ntau tau nce hauv db/db nas, ib qho qauv ntawm hom II DM (Sumi li al. 2011). Peb tau qhia txog kev sib koom ua ke ntawm PAR qhia thiab eNOS deficiency hauv cov nas mob ntshav qab zib (Oe li al. 2016). Kev qhia theem ntawm Par1 mRNA tau nce siab dua hauv eNOS-/-; Ins2Akita/+ nas dua hauv eNOS−/−; Ins2Akita/+ thiab cov nas uas tsis yog DM. Ib yam li ntawd, qhov kev qhia ntawm Par2 tau nce siab dua hauv eNOS−/−; Ins2Akita/+ nas tshaj cov nas uas tsis yog DM. Hauv qhov sib piv, Par4 mRNA qib tsis txawv ntawm cov genotypes. Qhov tsis muaj eNOS ua rau mob hnyav hauv DKD (Wang li al. 2011a). Vim hais tias pro-inflammatory cytokines tau tshaj tawm tias nce PARs (Nystedt li al. 1996), nce qhov mob tshwm sim los ntawm qhov tsis muaj eNOS yuav ua rau lub raum Pars qhia hauv DKD. Sib sau ua ke, cov txiaj ntsig ntawm peb cov kev tshawb fawb pom tau hais tias qib kev qhia ntawm PAR1 thiab PAR2, zoo ib yam li cov ntaub ntawv ntawm TF, tau nce hauv cov ntshav qab zib raum thaum eNOS tsis muaj (Fig. 2).
PAR2 Deletion Ameliorated Mob Ntshav Qab Zib Raum Kev Kho Mob hauv nas nrog Txo eNOS
Peb thiab lwm tus tau hais txog lub luag haujlwm ntawm PAR2 hauv DKD hauv kev kawm dhau los. Par2 deletion tsis cuam tshuam rau glomerular raug mob hauv cov kab mob ntshav qab zib hom Akita nas (Ins2Akita/+) nrog eNOS (Oe li al. 2016). Tsis tas li ntawd, STZ-vim cov nas mob ntshav qab zib tsis muaj PAR2 pom tias txo qis albuminuria piv rau cov nas uas muaj ntshav qab zib hom 2, tab sis nce mesangial expansion (Waasdorp li al. 2017). Ua ke, cov txiaj ntsig no qhia tau tias tsis muaj lossis tsis muaj kev kho mob me me ntawm PAR2 inhibition ntawm lub raum raug mob hauv cov qauv me me ntawm DKD. Hauv qhov sib piv, peb tau pom qhov cuam tshuam ntawm PAR2 deficiency ntawm DKD hauv cov nas mob ntshav qab zib Akita nrog kev txo qis ntawm eNOS (eNOS+/-; Ins2Akita/+) (Oe et al. 2016). Qhov tsis muaj PAR2 txo qis cov qib ntawm cov zis albumin tawm, mesangial expansion, thiab tuab ntawm GBM. Cov kev qhia theem ntawm pro-inflammatory thiab fibrosis ntsig txog cov noob, suav nrog Tnfa, Tgfb, thiab Col4, kuj raug txo qis hauv nas raum. Cov kev tshawb pom no qhia tias PAR2 yog cov kab mob tsis tshwm sim thaum ntxov, tab sis nyob rau hauv cov mob ntshav qab zib glomerular raug mob los ntawm eNOS tsis txaus (Table 1).
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