Qhov thib ob Endothelial Cell Dysfunction Thiab Ua Rau Cov Kab Mob Ntshav Qab Zib hauv cov neeg mob uas muaj kab mob raum ntev

TSHUAJ TIV THAIV ENDOTHELIAL Cell DYSFUNCTION hauv CKD

Endothelial cell dysfunction nyob rau hauv cov ntsiab lus ntawm CKD tau raug tshawb xyuas ntau yam hauv kev tshawb fawb tsiaj thiab hauv cov neeg mob (Table 1). Zuag qhia tag nrho, cov kev tshawb fawb no tau nthuav tawm txo qis endothelium-dependent vasodilation, endothelial glycocalyx kev puas tsuaj, nce endothelial permeability nrog rau nce proinflammatory thiab prothrombotic zog. Nrog rau macrovascular endothelial cell dysfunction, CKD yog txuam nrog microvascular dysfunction thiab rarefaction. Tsis tas li ntawd, cov neeg mob CKD tau nce ntxiv nrog rau qhov nruab nrab calcification, uas tau cuam tshuam nrog kev nce siab ntawm cov hlab ntsha.77,78 Ua ke nrog cov yam ntxwv ntawm cov phab ntsa vascular thiab lub cev tiv thaiv kab mob, 79 cov kev hloov pauv pathophysiological underlies lub zeem muag ntawm CKD raws li tus txheej txheem ntawm nce vascular laus.80

1. Kev Pom Zoo Los Ntawm Kev Kawm Tsiaj

Tsiaj qauv ntawm CKD tau muab rau peb nrog ntau yam kev pom zoo rau CKD-induced endothelial cell dysfunction raws li lawv tso cai rau hauv vivo kev ntsuam xyuas ntawm endothelial (cell) muaj nuj nqi. Induction ntawm CKD nyob rau hauv nas tau pom tias ua rau kom txo qis endothelium-dependent so, 81 nce endothelial permeability ntawm thoracic aorta, 82 thiab nce microvascular permeability uas tau ua ke rau kev poob ntawm endothelial nto txheej hauv cov qauv nas. ntawm proteinuric raum kab mob.83 Tsis tas li ntawd, kev puas tsuaj loj rau glycocalyx tau pom nyob rau hauv 5/6-nephrectomized nas, qhia los ntawm qhov txo qis ntawm aortic glycocalyx thiab nce qib ntawm glycocalyx tivthaiv syndecan-1 hauv plasma .84 Tsis tas li ntawd, nyob rau hauv nas qauv ntawm CKD, endothelial cell dysfunction tau pom nyob rau hauv macro- thiab microvascular theem, qhia los ntawm ib tug tseem ceeb txo nyob rau hauv glycocalyx thickness thiab ceev, ib tug upregulated qhia ntawm glycocalyx Cheebtsam, txo endothelium-dependent so nyob rau hauv teb rau acetyl. ntawm aortic rings thiab nce endothelial qhia ntawm ICAM-1 thiab VCAM-1.85–87 Ntxiv mus, siv microcomputed tomography duab ntawm cov hlab ntsha preglomerular, Ehling thiab al47 qhia tias lub raum tsis ua haujlwm ua rau txo qis hauv cov hlab ntsha. txoj kab uas hla thiab cov hlab ntsha branching nrog rau kev nce hauv cov hlab ntsha tortuosity hauv 3 murine qauv ntawm cov kab mob hauv lub raum thiab lub raum fibrosis. Ua ke nrog Apolipoprotein E-tsis muaj keeb kwm yav dhau los, CKD induction ntxiv ua rau lub nra hnyav dua, qhia tias muaj kev pheej hmoo ntawm atherosclerotic ntau dua hauv CKD.85.

2. Kev Pom Zoo Los Ntawm Kev Kawm Tus Neeg Mob

2.1 Txo Macrovascular Endothelium-Dependent Vasodilation hauv CKD

Raws li cov lus teb ua haujlwm ntawm peripheral microvasculature, raws li kev soj ntsuam los ntawm FMD, ntau qhov kev tshawb fawb tau pom tias cov neeg mob CKD muaj qhov cuam tshuam loj hauv endothelium-dependent vasodilation, 62-64 uas nce nrog nce CKD qhov hnyav, 64,88 ntawm nws tus kheej kwv yees cov txiaj ntsig ntawm cov hlab plawv 64 thiab correlates nrog sab laug ventricular hypertrophy.65 Tsis tas li ntawd, endothelium-independent vasodilation raws li ntsuas los ntawm brachial FMD tsom xam raws li kev txhaj tshuaj nitroglycerin tau txo qis hauv cov neeg mob CKD-tab sis tsis yog rau cov neeg mob uas muaj kab mob plawv thiab lub raum noj qab haus huv - nrog rau vascular calcification pom zoo raws li ib tug Muaj peev xwm hauv qab mechanism.89 Tsis tas li ntawd, ntau qhov kev tshawb fawb pom tau tias thaum CKD nce arterial txhav nce, 67,68,70 txawm hais tias lwm tus tsis tuaj yeem paub meej tias muaj kev sib raug zoo ntawm PWV thiab lub raum ua haujlwm tom qab hloov kho covariates (xws li, tab sis tsis txwv rau, hnub nyoog, poj niam txiv neej. , comorbidities, thiab siv tshuaj).69

Nyem qhov no kom tau txais cov teebmeem ntawm Cistanche ntawm lub raum

2.2 MVD thiab Rarefaction hauv CKD

CKD tau cuam tshuam nrog kev ua haujlwm tsis zoo ntawm ob qho tib si peripheral nrog rau coronary microvasculature thiab raws li CKD nce qib ntawm cov qauv thiab kev ua haujlwm capillary ntom ntom.49,59,90 Hauv tib neeg myocardial specimens ntawm CKD cov neeg mob, microvascular ntom tau pom tias txo qis los ntawm qhov nruab nrab 32 feem pua ​​49; Nws tuaj yeem raug pom nyob rau hauv CKD3-4 thiab tau nrog los ntawm kev hloov pauv ntawm endothelial-to-mesenchymal thiab myocardial fibrosis.49,91 Txawm hais tias cov neeg mob CKD feem ntau tuaj nrog comorbidities uas ua rau muaj kev loj hlob ntawm MVD (xws li, kub siab thiab ntshav qab zib), CKD-induced MVD - lossis uremic angiopathy - txuas ntxiv tshaj li cov xwm txheej no, nrog rau kev ua haujlwm tsis zoo ntawm microvasculature ntxiv rau kev loj hlob ntawm CKD. Cov ntaub ntawv pov thawj yog muab los ntawm cov qauv tsiaj ntawm CKD zoo li los ntawm CKD cov neeg mob kev tshawb fawb uas nws tau pom tias CKD-induced microvascular rarefaction tshwm sim nyob rau hauv ib tug heterogeneous qauv uas ua rau kev loj hlob ntawm loj avascular cheeb tsam.48,49

Kev ntsuas venous thiab ntiv tes plethysmography qhia tau hais tias muaj kev cuam tshuam endothelium-dependent vasodilatory teb nyob rau hauv nondialysis-dependent CKD, 61,66 txawm hais tias Wang thiab al92 tsis tau soj ntsuam kev sib raug zoo ntawm kwv yees GFR thiab reactive hyperemia index raws li ntsuas los ntawm peripheral arterial tonometry. Kev tsom mus rau cov kab mob microvascular dysfunction, kev tshuaj xyuas tsis ntev los no nrog kev tshuaj ntsuam xyuas meta tau qhia tias cov neeg mob CKD muaj qhov qis qis qis qis dua piv nrog cov neeg mob uas tsis yog CKD.59 Raws li nyob rau hauv cov pej xeem, txo qis coronary flow reserve raws li kev nyeem ntawv ntawm coronary microvascular dysfunction yog. Kev kwv yees txog kev pheej hmoo ntawm cov hlab plawv hauv cov neeg mob CKD, txawm tias tom qab hloov kho cov kab mob plawv.60,93 Restoration ntawm lub raum ua haujlwm raws li kev hloov hauv lub raum ib nrab ameliorated microvascular muaj nuj nqi raws li kev soj ntsuam ntawm sublingual microcirculation thiab coronary flow reserve, qhia tias qee yam. microvascular hloov hauv CKD yog thim rov qab.94,95

2.3 Endothelial Glycocalyx Kev puas tsuaj hauv CKD

Hauv cov neeg mob uas muaj CKD, nce qib ntawm glycocalyx Cheebtsam syndecan-1 thiab hyaluronan ua ke nrog kev ua haujlwm siab hyaluronidase tau kuaj pom hauv cov ntshav, nrog rau qib siab tshaj plaws tau pom hauv cov neeg mob CKD ntawm kev lim ntshav.71,84,96 Ib yam nkaus. kab, kev kho mob ntawm tib neeg endothelial hlwb nyob rau hauv vitro nrog uremic serum los ntawm pediatric CKD cov neeg mob los yog cov neeg laus hemodialysis coj mus rau ib tug txo nyob rau hauv glycocalyx qhov siab thiab stiffening ntawm endothelial hlwb.97 Glycocalyx kev puas tsuaj tau lees paub nyob rau hauv dermal biopsies ntawm CKD cov neeg mob, nyob rau hauv uas ib tug loj heev. Kev txo qis hauv staining nrog ulex europaeus agglutinin-1 (ib qho lectin khi glycoproteins thiab glycolipids) tau pom nyob rau hauv biopsies tau los ntawm nondialysis-dependent CKD cov neeg mob nrog rau cov neeg mob hemodialysis.98 Kev ntsuas ntawm thaj tsam perfused ciam teb, raws li qhov taw qhia ntawm thickness ntawm glycocalyx, tsis tshua muaj raws li cov kev tshawb fawb. Thaum Vlahu thiab al96 pom qhov nce ntawm thaj tsam perfused thiab perfused txoj kab uas hla, Liew thiab al71 pom tsis muaj qhov sib txawv tseem ceeb hauv thaj tsam perfused. Peb lub hlis tom qab hloov lub raum, cov cim ntawm endothelial glycocalyx tau txhim kho raws li thaj tsam perfused ciam teb txo qis thiab cov ntshav syndecan-1, sVCAM{11}}, thiab vWF qib tau txo qis hauv kev sib piv rau qib pretransplant.99 Serum hyaluronan qib tseem nyob. tsis hloov.99

Cistanche extract capsules

2.4 Soluble Biomarkers ntawm Endothelial Health hauv CKD

Cov kab mob biomarkers tau siv los muab kev nkag siab txog qhov ua haujlwm ntawm endothelial cell dysfunction hauv cov neeg mob uas muaj kev pheej hmoo siab plawv (Table 1). Kev ua haujlwm tsis zoo ntawm endothelium feem ntau tsim tsawg NO los ntawm kev txo qis lossis kev ua haujlwm ntawm eNOS, tab sis qhov luv luv ib nrab-lub neej ntawm NO ua rau nws nyuaj rau kev ntsuam xyuas qhov tseeb ntawm endothelial cell function. Lwm cov txheej txheem biomarkers uas tau siv thaum kawm endothelial cell dysfunction muaj xws li shredded cov ntaub ntawv ntawm o-induced cell nto adhesion receptors (xws li, soluble forms ntawm VCAM-1, ICAM-1, P-selectin, thiab E- selectin, nrog rau tom kawg suav tias yog qhov xaiv tshaj plaws rau cov hlwb endothelial).100 Nrog rau cov endothelium ua si lub luag haujlwm tseem ceeb hauv hemostasis, cov molecules koom nrog hauv platelet activation thiab coagulation feem ntau raug ntsuas kom ntsuas cov lus teb thrombotic ntawm qhov muaj feem cuam tshuam txog endothelium. Qhov no suav nrog cov theem ntawm vWF, soluble thrombomodulin, tPA (cov ntaub so ntswg-hom plasminogen activator), thiab PAI -1 (plasminogen activation inhibitor-1; fibrinolysis inhibitor).100,101 Txawm li cas los xij, nws yuav tsum tau muab sau tseg tias feem ntau. ntawm cov kab mob biomarkers tsis yog tshwj xeeb rau cov kab mob endothelium puas thiab tsuas yog muab kev nkag siab tsis ncaj rau hauv lub peev xwm endothelial cell dysfunction.

Tshwj xeeb hauv cov neeg mob uas tsis yog mob ntshav qab zib hauv CKD theem 3-5, plasma thiab ntshav ntshav qib asymmetric dimethylarginine (ib qho eNOS inhibitor), L-arginine (tus ua ntej ntawm NO), sVCAM-1, sE-selectin, sP -selectin, s-thrombomodulin, tPA, uPA (urokinase-type plasminogen activator), TF thiab vWF tau nce siab (Table 1).71–73,75,76,102 Cov cim ntawm endothelial activation muaj feem cuam tshuam nrog albuminuria thiab txo qis GFR. Raws li cov cim rau CKD qhov hnyav.62,71 Txawm tias qhov mob me me hauv lub raum kev ua haujlwm tau cuam tshuam nrog nws tus kheej nrog cov qib plasma ntawm vWF thiab sVCAM-1 raws li cov cim ntawm endothelial activation.74 Cov teebmeem ntawm CKD ntawm cov kab ke ntawm PAI{{18} }} thiab sICAM-1 tsis tshua meej, sib txawv ntawm qhov tsis hloov pauv 62,74,76 mus rau qib nce ntxiv hauv cov neeg mob uas tsis yog mob ntshav qab zib CKD.73,75

MECHANISTIC INSIGHTS RAU ENDOTHELIAL Cell DYSFUNCTION IN CKD

Kev sib txawv ntawm cov txheej txheem pathophysiological tau raug txheeb xyuas los pab txhawb rau endothelial cell dysfunction hauv CKD. Cov no suav nrog kev mob qis qis, nce oxidative kev nyuaj siab, tsub zuj zuj ntawm uremic toxins, thiab cuam tshuam posttranslational hloov ntawm cov proteins thiab lipoprotein hais, nrog rau metabolic acidosis thiab siab sympathetic activation (Daim duab 3 txog 5). Tsis tas li ntawd, cov neeg mob uas muaj CKD pom cov tsos mob ntawm vascular laus thiab tam sim no nrog vascular calcification. Hauv kab lus hauv qab no, kev sib cuam tshuam ntawm txhua qhov sib txawv no nrog kev ua haujlwm ntawm endothelial cell dysfunction hauv CKD. Cov teebmeem ntawm cov kab mob plawv ib txwm muaj xws li ntshav siab thiab ntshav qab zib mellitus raws li kev sib xyaw ua ke thiab ua rau CKD, tsis tau tham txog.

Cistanche tubulosa

Chronic Low-Grade Inflamation

Nyob rau hauv lub raum puas, unsolved qis-qib o ua rau cov neeg nyob rau hauv lub raum hlwb los tsim proinflammatory cytokines thiab chemokines thiab induce lub deposition ntawm ECM pab mus rau tubulointerstitial fibrosis. Yog li ntawd, qhov mob qis qis qis yog qhov tseem ceeb ntawm CKD kev loj hlob.60 Tsis tas li ntawd, qhov txo qis pom kev ua haujlwm ntawm ob lub raum hauv CKD ua rau lub cev muaj zog uremic milieu, uas ua rau cov kab mob tsis zoo, mob qis qis los ntawm kev hloov cov lus qhia thiab tso tawm. proinflammatory mediators, xws li cytokines, nyob rau hauv cov ntshav.103 Hallmarks ntawm low-grade o hauv CKD yog elevated systemic theem ntawm cov proinflammatory cytokines IL-1 , IL-6, TNF (tumor necrosis factor)- , thiab hs-CRP (high-rhiab heev C-reactive protein), uas muaj nyob rau hauv cov ntshav vim muaj kev tso tawm ntau ntxiv nrog rau txo qis raum tshem tawm.104,105

Cov kab mob proinflammatory biomarkers cuam tshuam nrog CKD kev nce qib 106 nrog rau kev pheej hmoo plawv hauv cov neeg mob nrog CKD.107 Piv txwv li, cov qib ntshav ntawm hs-CRP tuaj yeem kwv yees cov xwm txheej ntawm cov hlab plawv hauv cov neeg mob CKD, 108,109 nrog kev kho mob txaus ntshai ntawm 1.94 rau cov hlab plawv tuag ntau dua. Kev soj ntsuam nruab nrab ntawm 10 xyoo rau CKD3-4 cov neeg mob uas muaj CRP siab (Ntau dua lossis sib npaug li 3 mg / L) piv nrog qis CRP (<3 mg/L).109 Also, systemic levels of IL-6 correlated with a poor outcome in CKD, and both IL-6 and TNF-α could predict all-cause mortality in CKD5D patients after adjustment for age, sex, diabetes, smoking, baseline kidney function, protein-energy wasting as well as other inflammation biomarkers as hsCRP (high-sensitivity C-reactive protein).104,107 On the other hand, also the antiinflammatory IL-10 is upregulated in patients with CKD through increased secretion by uremic monocytes and reduced kidney clearance, with IL-10 counteracting the activated inflammatory response.104 Increased IL-10 levels were found to be positively correlated with cardiovascular events in CKD patients at follow-up, with increased IL-10 levels interpreted as an increased compensatory effect in an overall proinflammatory state in CKD patients.110

Antibody-mediated blockade ntawm IL-1 hauv CANTOS sim (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) txo qhov tshwm sim ntawm cov teeb meem mob plawv loj hauv cov neeg mob nrog cov neeg mob nruab nrab CKD (CKD3a) dhau qhov kev soj ntsuam ntawm 3.7 xyoo. .111 Thaiv IL-6 rau 24 lub lis piam nyob rau hauv cov neeg mob nrog CKD3-5D thiab residual inflammatory kev pheej hmoo nyob rau hauv RESCUE sim txo hs-CRP raws li ib tug systemic o marker, nrog rau kev tshawb fawb ZEUS (Zlitivekimab Cardiovascular Outcomes Study ) tam sim no ntsuas qhov txiaj ntsig zoo ntawm cov txiaj ntsig ntawm cov hlab plawv hauv CKD3-4 cov neeg mob uas muaj kev pheej hmoo ntawm cov kab mob residual.112

Cistanche tshuaj thiab qhuav Cistanche

Kev mob o thiab cov cytokines tau hais los saum toj no yog txuas nrog endothelial o thiab endothelial cell dysfunction. Piv txwv li, IL-6 paub tias yuav ua rau CRP ntau lawm, nrog rau ob qho tib si IL-6113 thiab CRP114 txo qis endothelial ntau lawm thiab / lossis ua kom eNOS thiab yog li NO yog ib qho tseem ceeb molecule hauv kev saib xyuas vascular noj qab haus huv. IL-6 kuj tseem ua rau cov kab mob endothelial tsis zoo thiab ua kom cov kab mob endothelial permeability los ntawm kev txo cov kab mob endothelial ntawm adherens junction protein VE-Cadherin ntawm trans-signaling pathway115 nrog rau kev sib txuas lus hauv zos ntawm cov protein sib txuas nruj ZO{{7} } ntawm STAT3 phosphorylation.116 TNF- txo qis endothelial-dependent vasodilation ntawm nas aortas los ntawm kev tsim cov superoxide los ntawm kev ua kom NADPH oxidases, 117 thiab ob qho tib si nce TNF- thiab txo NO tuaj yeem cuam tshuam rau endothelial apoptosis hauv cov hlab ntsha hnub nyoog 18 xyoo.

Ntxiv rau cov qib cytokine siab, cov neeg mob uas muaj CKD tso saib nce qib ntawm kev phom sij cuam tshuam nrog cov qauv molecules xws li HMGB1, S100 proteins, thiab qib siab glycation endproducts (AGEs), uas ua rau muaj kev cuam tshuam cov lus teb dhau RAGE (receptor rau qib siab glycation endproduct), TLRs. , thiab NLRP3 inflammasome activation.119,120 Tsis tas li ntawd, neutrophil extracellular ntxiab raws li tsim los ntawm activated neutrophils induce endothelial o thiab txhim kho TF qhia thiab kev ua ub no, yog li txhawb coagulation.121 Lwm contributors rau ib tug mob inflammatory xeev nyob rau hauv CKD yog gut79 co toxins (gut 7 dysbiosis). tau tham ntau yam hauv qab no).

Lub xeev qis qis tsis yog pom nyob hauv CKD nkaus xwb, tab sis kuj tseem muaj lwm yam kab mob ntev nrog rau kev laus, thiab yog li hu ua inflammageing.79 Zuag qhia tag nrho, qib qis qis ua rau cov kab mob endothelial tsis ua haujlwm nrog rau oxidative kev nyuaj siab, uas nyob rau hauv lem amplifies lub xeev inflammatory, raws li tau tham ntxiv hauv qab no.

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Constance CFMJ Baaten, Sonja Vondenhoff, Heidi Noels