Coagulation, Protease-Activated Receptors, Thiab Mob raum Ntshav Qab Zib: Cov Lus Qhia Los Ntawm ENOS-Deficient nas

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). Rau kev xeemple, upregulation ntawm TLR4-NF-kB txoj hauv qabkab mob metaboliccov xwm txheej nce TF qib (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). Tsom ntsoov rau kev sib raug zoo ntawm coagulation, eNOS, thiabdyslipidemia, 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 thiabkev raug mob histological, uas tau ntxiv exacerbated los ntawm kev noj zaub mov muaj rog. 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 hauvkev sib koom ua ke. Interestingly, colocalization thwmsim nrog glomerular monocyte / macrophage marker pom tau tias nce qib ntawm immunoreactive TF.

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 elucidate 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.ntshav qab zib raumhauv eNOS-tsis muaj nas (Li et 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.

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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, qhov txwv redox 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 hauv hom I.cov nas mob ntshav qab zib.

Lwm yam Coagulation Factors hauv DKD

Vim tias thrombin lub hom phiaj yog PAR1, uas nce ntxivvascular mob(Chen thiab Dorling 2009),thrombin yuav exacerbates DKD. Txawm li cas los xij, txoj haujlwm tiv thaiv lossis teeb meem ntawm thrombin hauv DKD pathogenesis tau tshwm sim; Tsis tshua muaj tshuaj thrombin (50 pM) tiv thaiv, whereas high-dose thrombin (20 nM) aggravated,Glucose-induced apoptosishauv 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 ntau yaminflammatory xwm txheej. 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 haujlwm hauvDKD kab mobtsim nyog kev 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 qhov kev qhia theem ntawm Par1 thiab / lossis Par2 mRNA tau nce hauv cov qauv tsiaj nrog mob ntshav qab zib nephropathy, adenine-induced raum raug mob, obstructive raum fibrosis, thiab cisplatin-induced raum raug mob (Chung et al. 2013; Hayashi et 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 Diabetic raum

Kev raug 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 tau pom tias txo qis albuminuria piv rau cov kab mob ntshav qab zib hom nas tab sis nce lub hom phiaj nthuav dav (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).

Dual Blockade ntawm PAR1 thiab PAR2 hauv cov nas mob ntshav qab zib nrog Txo eNOS

Peb tau pom tias PAR1 thiab PAR2 koom tes nrog DKD pathogenesis (Mitsui li al. 2020). Hauv txoj kev tshawb no, txiv neej hom I ntshav qab zib Akita nas heterozygous rau eNOS (Ins2Akita/+; eNOS+/-) tau siv los ua tus qauv ntawm DKD. Cov nas no tau kho nrog lub tsheb, PAR1 antago nist (E5555, 60 mg / kg / hnub), PAR2 antagonist (FSLLRY, 3 mg / kg / hnub), lossis E5555 + FSLLRY rau 4 lub lis piam. Kev tswj hwm ntawm PAR1 lossis PAR2 antagonist ib leeg txo qis glomerular raug mob, xws li mesangial expansion thiab collagen IV deposition, piv rau kev tswj hwm lub tsheb. Synergistic therapeutic teebmeem ntawm ob qho tib si PAR1 thiab PAR2 inhibition tau pom, thiab cov zis albumin-to-creatinine piv tau txo qis thaum ob qho tib si PAR1 thiab PAR2 raug thaiv nrog E5555 + FSLLRY piv nrog kev tswj hwm tsheb. Tsis tas li ntawd, ob qhov thaiv ntawm PAR1 thiab PAR2 los ntawm E5555 + FSLLRY synergistic cally ameliorated histological raug mob, suav nrog mesangial expansion, glomerular macrophage infiltration, thiab deposition ntawm hom IV collagen. Cov kev qhia theem ntawm o- thiab fibrosis-hais txog cov noob hauv lub raum kuj raug txo qis (Table 1).

Peb tsom mus rau cov kev mob tshwm sim ntawm PAR1 thiab PAR2 agonists ntawm tib neeg cov kab mob endothelial (Mitsui li al. 2020). Cov txiaj ntsig tau pom tias kev txhawb nqa nrog PAR1 thiab PAR2 agonists synergistically nce qib ntawm MCP1 thiab PAI1 mRNA. Cov nyhuv ntawm PAR1 agonist raug thaiv los ntawm NF-κB inhibitor, thaum PAR2 agonist raug thaiv los ntawm NF-kB thiab MAPK inhibitors. Sib sau ua ke, PAR1 thiab PAR2 koom tes ua haujlwm rau vascular o thiab DKD los ntawm txoj kev sib txawv (Fig. 3).

Xaus

Hauv kev tshuaj xyuas no, peb tau tsom mus rau kev sib raug zoo ntawm coagulation protease-PAR txoj hauv kev thiab eNOS deficiency hauv cov nas mob ntshav qab zib. Kev tsim tawm qis ntawm eNOS yog txuas rau hypercoagulability thiab nce PAR signaling, uas yog teeb meem rau DKD. Cov kev tshawb pom no yuav qhia tau tias lawv lub luag haujlwm pathological nyob rau theem siab lossis tom qab ntawm DKD (xws li, nrog rau lub raum tsis ua haujlwm thiab / lossis cov proteinuria loj). Qhov ncauj FXa inhibitors yog dav siv los tiv thaiv thrombosis (Patel li al. 2011; Robertson li al. 2015). Lawv siv rau hauv kev kho mob ntawm DKD yog qhov kev xaiv zoo. Tsis tas li ntawd, qee qhov PAR1 antagonists, suav nrog atopaxar thiab vorapaxar, tuaj yeem siv rau hauv kev kho mob antiplatelet los tiv thaiv kev mob plawv (Goto li al. 2010; Tricoci li al. 2012). Tsis tas li ntawd, muaj qhov ua tau zoo tshaj plaws hauv kev txhim kho PAR2 antagonists (Lim li al. 2013; Cheng et al. 2017; Jiang et al. 2018), thiab lawv tuaj yeem yog cov kev xaiv kho tshiab los kho cov neeg mob DKD.

Kev lees paub

Txoj kev tshawb no tau txhawb nqa los ntawm Gonryo Medical Foundation. Peb xav ua tsaug rau Editage (https://www. editage.com) rau kev kho lus Askiv.

Kev tsis sib haum xeeb ntawm kev txaus siab Cov neeg sau ntawv tshaj tawm tsis muaj teeb meem ntawm kev txaus siab.

Cov ntaub ntawv

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M., Kretzler, M., Leiter, EH, Levi, M., McIndoe, RA, Sharma, K., Smithies, O., Susztak, K., et al. (2009) nas qauv ntawm ntshav qab zib nephropathy.J. Am. Soc. Nephrol., 20, 2503-2512 ib. Cameerer, E., Huang, W. & Coughlin, SR (2000) Tissue factor and factor X-dependent activation of protease-activated receptor 2 by factor VIIa.Proc. Natl. Acad. Sci. Teb chaws USA, 97, 5255-5260. 

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Xwm, 545, 112-115 ib. Chung, H., Ramachandran, R., Hollenberg, MD & Muruve, DA (2013) Proteinase-activated receptor-2 transactivation of epidermal growth factor receptor thiab transforming growth factor- receptor signaling pathways pab txhawb rau lub raum fibrosis.J. Biol. Chem., 288, 37319-37331 ib. Coughlin, SR (2005) Protease-activated receptors hauv hemostasis, thrombosis thiab vascular biology.J. Taub. Haemost., 3, 1800-1814 ib. Craciun, FL, Ajay, AK, Hoffmann, D., Saikumar, J., Fabian, SL,

Bijol, V., Humphreys, BD & Vaidya, VS (2014) Pharmaco logical and genetic depletion of fibrinogen tiv thaiv lub raum fibrosis.Am. J. Physiol. Lub raum Physiol., 307, 

F471- 484. Cunningham, MA, Rondeau, E., Chen, X., Coughlin, SR, Hold sworth, SR & Tipping, PG (2000) Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renalitis in crescentic glomerulonephritis.J. Exp. Med., 191, 455-462.