Kev nkag siab tshiab rau hauv Kev Tiv Thaiv Kev Ua Haujlwm ntawm Podocytes: Lub luag haujlwm ntawm kev ntxiv

Abstract

Podocytes yog qhov sib txawv ntawm cov hlwb epithelial uas ua lub luag haujlwm tseem ceeb hauv kev ua kom lub cev ua haujlwm ntawm glomerular filtration barrier (GFB). Ntxiv nrog rau lawv cov khoom nplaum hauv kev tswj xyuas kev ncaj ncees ntawm qhov pom kev thaiv, lawv muaj lwm yam haujlwm, xws li kev sib txuas ntawm cov khoom ntawm glomerular hauv qab daus daim nyias nyias (GBM), tsim cov vascular endothelial kev loj hlob zoo (VEGF), tso tawm cov inflammatory proteins, thiab nthuav qhia cov khoom ntxiv. Lawv kuj koom nrog hauv glomerular crosstalk los ntawm ntau txoj kev taw qhia, suav nrog endothelin-1, VEGF, hloov pauv kev loj hlob (TGF), pob txha morphogenetic protein 7 (BMP-7), latent transforming growth factor -binding protein 1 (LTBP1), thiab extracellular vesicles. Cov ntaub ntawv loj hlob qhia tau hais tias podocytes qhia ntau yam khoom ntawm lub cev thiab kev tiv thaiv kab mob, txhawb nqa ntau lub luag haujlwm hauv kev ua kom lub cev noj qab haus huv glomerulus. Raws li qhov tshwm sim, qhov "immune podocyte" dysfunction yog xav tias yuav koom nrog hauv cov kab mob ntawm ntau cov kab mob glomerular, hu ua "podocytopathies." Ntau yam xws li cov neeg kho tshuab, oxidative, thiab/los yog cov tshuaj tiv thaiv kab mob tuaj yeem ua rau mob hlwb.

Cov txiaj ntsig ntawm cistanche tubulosa- ua kom muaj zog tiv thaiv kab mob

Cov txheej txheem ntxiv, ua ib feem ntawm ob qho tib si hauv lub cev thiab kev tiv thaiv kab mob, kuj tseem tuaj yeem txhais cov kev puas tsuaj ntawm podocyte los ntawm ntau lub tswv yim, xws li reactive oxygen hom (ROS) tiam, cytokine ntau lawm, thiab endoplasmic reticulum kev nyuaj siab, thaum kawg cuam tshuam rau kev ncaj ncees ntawm cytoskeleton, nrog rau tom qab. podocyte detachment los ntawm GBM thiab pib ntawm proteinuria. Interestingly, podocytes tau pom tias yog ob qho tib si qhov chaw thiab lub hom phiaj ntawm kev sib koom ua ke ntawm kev raug mob. Podocytes nthuav qhia cov protein ntau ntxiv uas ua rau kev ua kom muaj zog hauv zos. Nyob rau tib lub sijhawm, lawv cia siab rau ntau lub tswv yim tiv thaiv kom dim qhov kev puas tsuaj no. Podocytes qhia txog qhov ua tau zoo H (CFH), ib qho ntawm cov tswj hwm tseem ceeb ntawm cov khoom siv ntxiv, nrog rau cov txheej txheem sib txuas ua ke zoo li CD46 lossis membrane cofactor protein (MCP), CD55 lossis decay-accelerating factor (DAF), thiab CD59 lossis tiv thaiv. Cov txheej txheem ntxiv, xws li autophagy lossis actin-based endocytosis, kuj tseem koom nrog txhawm rau txhawm rau txhawm rau txhim kho podocyte homeostasis thiab tiv thaiv kev raug mob. Qhov kev tshuaj xyuas no yuav muab cov ntsiab lus ntawm lub cev tiv thaiv kab mob ntawm podocytes thiab lawv cov lus teb rau kev tiv thaiv kab mob hauv nruab nrog cev, tsom rau cov kab mob sib txuas ntawm kev sib ntxiv thiab kev puas tsuaj podocyte.

cistanche ntxiv cov txiaj ntsig-nce kev tiv thaiv

Nyem qhov no mus saib Cistanche Enhance Immunity khoom

【Nug ntxiv】 Email: cindy.xue@wecistanche.com / Whats App: 0086 18599088692 / Wechat: 18599088692

Ntsiab lus Podocyte, Complement, Immune system

Keeb kwm

Podocytes yog cov hlwb tshwj xeeb ntawm cov glomerulus thiab sawv cev rau ib feem tseem ceeb ntawm GFB [1]. Lawv muaj cov txheej txheem nyuaj nrog rau lub cev loj ntawm lub cev uas tig mus rau qhov chaw tso zis thiab kev sib txuas sib txuas ntawm cov txheej txheem txuas ntxiv (thawj thiab theem nrab txheej txheem) xaus li (tertiary) cov txheej txheem ko taw ntawm GBM [2]. Ib txwm ua haujlwm podocyte tau lees paub los ntawm kev ua haujlwm zoo ntawm actin cytoskeleton, feem ntau nyob hauv cov txheej txheem ko taw [3]. Podocytes yog tus cwj pwm los ntawm cov txheej txheem nyuaj heev uas tswj hwm los ntawm ntau cov proteins, muab faib ua ob lub ntsiab ntawm cov qauv podocyte: lub slit diaphragm (SD) thiab focal adhesions (FA). SD yog ib qho tshwj xeeb tshwj xeeb ntawm cov xov tooj ntawm tes sib txuas ntawm ob txoj haujlwm podocyte ko taw (Daim duab 1), suav nrog cov proteins tseem ceeb xws li nephrin, podocin, lossis synaptopodin [4, 5]. Lub SD sawv cev tsis yog tsuas yog qhov loj-xaiv teeb meem los tiv thaiv kev pom ntawm cov macromolecules loj, tab sis kuj yog lub teeb pom kev zoo nrog lub luag haujlwm tseem ceeb, xws li kev tswj hwm ntawm actin cytoskeleton thiab pib ntawm kev taw qhia txoj hauv kev los hloov kho cov txheej txheem ntawm ko taw [6]. FA yog cov txheej txheem nyuaj uas tuaj yeem txuas cov actin cytoskeleton ntawm cov txheej txheem ko taw mus rau GBM, ua tsaug rau ob lub ntsiab molecular Cheebtsam: integrins thiab GTPases. Dhau li ntawm kev txhawb nqa GFB, podocytes ua haujlwm tseem ceeb xws li kev sib txuas thiab kho GBM (ua ke nrog cov hlwb endothelial), tsim cov VEGF, thiab platelet-derived growth factor (PDGF) [6–9]. Ntxiv mus, ib phau ntawv loj hlob qhia tias podocytes muaj ntau lub luag haujlwm hauv lub cev thiab hloov lub cev tsis muaj zog [10–13]. Lawv nthuav qhia cytokine thiab chemokine receptors los teb rau ntau yam kev sib haum xeeb soluble. Lawv kuj muaj peev xwm ua kom muaj cov kab mob sib kis, xws li interleukin-1 (IL{14}}), uas tuaj yeem ua rau mob hauv zos. Cov ntaub ntawv pov thawj hauv cov ntaub ntawv qhia txog lub luag haujlwm hauv lub cev tiv thaiv kab mob ib yam nkaus, raws li cov tshuaj tiv thaiv kab mob tam sim no (APC) pib cov lus teb tshwj xeeb T-cell, xws li dendritic cells lossis macrophages [14, 15]. Tsis tas li ntawd, podocytes nthuav qhia ntau yam ntxiv, xws li ntxiv receptor hom 1 (CR1) thiab hom 2 (CR2) thiab ntxiv cov tswj hwm zoo li CD46, CD55, lossis CD59, thiab lawv tuaj yeem tsim cov protein ntau hauv zos, suav nrog cov khoom ntxiv 3 (C3) thiab NWS [16–18]. Txawm li cas los xij, lub luag haujlwm ntawm cov ntsiab lus ntxiv tau qhia lossis zais los ntawm podocytes hauv kev tswj hwm ntawm cov tshuaj tiv thaiv hauv zos tsis tau nkag siab tag nrho. Kev raug mob Podocyte tau koom nrog hauv pathophysiology ntawm ntau cov kab mob glomerular, xws li kev tiv thaiv kab mob-complex glomerulonephritis, kev hloov pauv tsawg heev (MCD), focal segmental glomerulosclerosis (FSGS), thiab kev sib tsoo glomerulopathy [19, 20], thiab cov ntaub ntawv pov thawj los ntawm cov ntaub ntawv qhia tias cov khoom ntxiv. kab ke tuaj yeem yog thawj lossis theem nrab koom nrog hauv kev puas tsuaj podocyte [21–23].

Fig. 1 Cov khoom tseem ceeb ntawm cov kab mob slit diaphragm thiab podocyte-endothelial cell cross-hais lus hauv kev noj qab haus huv piv rau cov podocytes puas. Podocyte slit diaphragm, glomerular basement membrane (GBM), thiab endothelial hlwb yog cov khoom tseem ceeb ntawm glomerular filtration barrier. Podocyte effacement / detachment, theem nrab rau txhua yam, oxidative, thiab / los yog immunologic triggers, yog tus cwj pwm los ntawm kev poob ntawm silt diaphragm kev ncaj ncees, cuam tshuam ntawm actin cytoskeleton thiab focal adhesions, thiab cuam tshuam ntawm lub cev nqaij daim tawv podocyte-endothelial cellash cross-talk ( ). Cov ntawv luv: GBM, glomerular hauv qab daim nyias nyias; Yog, angiopoietin; ANGPTL, zoo li angiopoietin protein; IGF, kev loj hlob zoo li insulin; IGFBP-rP1, zoo li insulin-zoo li kev loj hlob zoo-binding protein-muaj protein ntau 1; ET-1, endothelin-1; HGF, hepatocyte loj hlob yam; IL-1, interleukin-1; Tsis yog, nitric oxide; TNF-a, qog necrosis factor-a; VEGF, vascular endothelial kev loj hlob yam

Lub cev tiv thaiv kab mob podocyte: innate thiab adaptive zog

cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob

Cov ntaub ntawv pov thawj ntxiv qhia tias podocytes ua lub luag haujlwm hauv lub cev tiv thaiv kab mob vim yog lawv qhov kev qhia ntawm Tus Xov Tooj Zoo li receptors (TLRs), tshwj xeeb tshaj yog TLR4, ib hom subtype muaj peev xwm paub txog cov kab mob lipopolysaccharide (LPS). Cov receptors yog upregulated nyob rau hauv cov tsiaj qauv ntawm cryoglobulinemic membranoproliferative glomerulonephritis, thiab lawv muaj peev xwm kho glomerular puas los ntawm modulating cov kev qhia ntawm chemokines [12]. TLRs nyob rau ntawm lub xov tooj ntawm tes los yog intracellularly thiab tuaj yeem qhia los ntawm ntau hom hlwb, xws li dendritic hlwb, macrophages thiab monocytes, fibroblasts, B thiab T hlwb, thiab endothelial thiab epithelial hlwb. Lawv ua lub luag haujlwm tseem ceeb hauv kev paub txog cov kab mob cuam tshuam nrog cov qauv molecular; tshwj xeeb, TLRs ntawm tes tuaj yeem paub txog cov kab mob microbial xws li LPS, lipids, thiab cov proteins, thaum TLRs intracellular feem ntau paub txog nucleic acids los ntawm cov kab mob thiab kab mob [24]. Tsis tas li ntawd, TLRs tuaj yeem ua haujlwm tau los ntawm cov ligands endogenous tso tawm thaum muaj kev ntxhov siab lossis cov ntaub so ntswg raug mob, xws li cov protein ua rau kub, mRNA, thiab cov khib nyiab necrotic [25]. Cultured human podocytes constitutively nthuav tawm cell nto TLRs (ie, TLR1, 2, 3, 4, 5, 6, thiab 10) [26], qhia txog lub luag haujlwm muaj peev xwm hauv kev tiv thaiv kab mob microbial; Txawm li cas los xij, de novo qhia ntawm intracellular TLRs subtype kuj tau tshaj tawm hauv podocytes ntawm cov neeg mob glomerular. Hauv particular, puromycin aminonucleoside (PAN), feem ntau yog siv los ua kom tsis muaj kab mob podocyte raug mob hauv vitro, tuaj yeem txhim kho TLR9 intracellular qhia thiab qhib NF-κB thiab p38 MAPK hauv tib neeg immortalized podocytes, siv endogenous mtDNA li TLR9 ligand7poptosis. ]. Qhov no yuav qhia txog lub luag haujlwm bivalent ntawm TLRs hauv podocytes, ob qho tib si raws li cov neeg tseem ceeb hauv kev teb rau cov kab mob txawv teb chaws thiab cov neeg nruab nrab ntawm kev puas tsuaj podocyte. Ntxiv mus, podocytes tuaj yeem nthuav qhia MHC chav kawm I thiab II noob [28, 29], nrog rau B7-1 (los yog CD80, koom nrog T-cell ua kom) [15, 30] thiab FcRn (IgG thiab albumin thauj receptor. , siv los ntawm podocytes rau internalize IgG los ntawm GBM) [31, 32]. Tshwj xeeb, MHC chav kawm II qhia ntawm podocytes yog xav tau rau kev txhim kho ntawm lub raum tsis muaj zog tiv thaiv kab mob, vim MHC II kev nthuav qhia los ntawm podocytes yog qhov tsim nyog los ua rau CD4+T-cell-driven glomerular kab mob [14]. Nws tau tshaj tawm tias cov hlwb no tuaj yeem ua raws li cov tshuaj tiv thaiv kab mob tam sim no (APC), vim tias lawv tuaj yeem nthuav qhia ntau cov cim macrophagic txuam nrog [33, 34], thiab lawv muaj peev xwm ua cov antigens los pib cov lus teb tshwj xeeb T-cell [15], txhawb lawv lub luag haujlwm multifunctional hauv kev tiv thaiv kab mob ntawm cov kab mob glomerular. Tsis tas li ntawd, kev qhia txog kev ua haujlwm ntawm chemokine receptors (CCR4, CCR8, CCR9, CCR10, CXCR1, CXCR3, CXCR4, thiab CXCR5) tau pom nyob rau hauv kab lis kev cai tib neeg podocytes [35, 36]. Chemokines yog cov chemoattractant cytokines me me tso tawm los ntawm lub cev tiv thaiv kab mob (piv txwv li, neutrophils, eosinophils, macrophages, dendritic cells, natural killer cells), as well as endothelial thiab epithelial cells. Tey ua lub luag haujlwm tseem ceeb hauv kev mob thiab kev tiv thaiv kab mob hauv lub cev los ntawm kev coj cov leukocytes mus rau qhov mob los yog puas tsuaj [37, 38]. Lawv kuj txhawb kev loj hlob ntawm tes thiab qog nqaij hlav angiogenesis thiab muaj peev xwm hloov kho apoptosis los ntawm kev khi G-protein-coupled receptors (GPCRs) nyob rau saum npoo ntawm lub cev tiv thaiv kab mob. Chemokine receptors yog qhia nyob rau hauv leukocytes, nrog rau cov hlwb uas tsis yog hemopoietic, xws li endothelial thiab epithelial hlwb [39].

CXCR1, CXCR3, thiab CXCR5 chemokine receptors tau pom nyob rau hauv podocytes los ntawm lub raum biopsies ntawm cov neeg mob uas muaj thawj membranous nephropathy (PMN), thaum lawv tsis tau qhia nyob rau hauv lub raum noj qab haus huv. Huber et al. qhia tias kev ua kom podocyte CXCRs tuaj yeem ua rau GFB cuam tshuam thiab pib ntawm proteinuria hauv PMN los ntawm hyperactivation ntawm NADPH oxidases thiab oxygen radicals ntau lawm [36]. Podocytes tau koom nrog hauv cov lus teb inflammatory ntawm ntau tus tib neeg glomerulopathies, raws li qhia los ntawm lawv lub peev xwm los tsim cov cytokines pro-inflammatory xws li IL-1 thiab IL-1 [40, 41]. Nws tau raug tshaj tawm tias lawv tuaj yeem nthuav qhia cov kab mob ua rau mob, xws li NOD-zoo li receptor (NLR) tsev neeg cov proteins, uas ua rau cov lus teb rau hauv lub raum hauv zos hauv cov kab mob glomerular xws li lupus nephritis (LN) [42]. Podocytes tseem paub txog kev zais thiab / lossis nthuav qhia ntau cov proteins thiab cov tswj hwm, qhia txog kev ua kom muaj zog hauv zos ntawm qhov sib ntxiv cascade. Kev nthuav qhia ntawm cov noob caj noob ces, suav nrog C1q, C1r, C2, C3, C3a receptor (C3aR), C5a receptor (C5aR), C7, CR1, thiab CR2, tau kuaj pom hauv kab lis kev cai podocytes nyob rau hauv ib txwm muaj lub cev muaj zog, nrog rau kev sib xyaw hauv zos ntawm kev sib ntxiv. proteins tom qab raug mob podocyte [16, 17]. Ntawm qhov tod tes, ntxiv cov tswj hwm tau raug txheeb xyuas ib yam nkaus, ob qho tib si daim nyias nyias (CD46, CD55, CD59) thiab cov ntaub ntawv soluble (CFI thiab CFH). Hauv particular, podocytes tuaj yeem nthuav qhia CFH hauv zos kom tshem tawm cov kab mob subendothelial tsis yooj yim tso nyiaj [43]. Qhov tseeb tias podocytes muaj peev xwm tsim cov khoom ntxiv, suav nrog cov tswj hwm, yuav muaj feem cuam tshuam rau podocytopathies qhov twg cov txheej txheem ntxiv ua lub luag haujlwm pathogenic. Qhov sib npaug ntawm kev ua kom muaj zog hauv zos thiab kev tswj hwm yog ib qho tseem ceeb los tswj lub glomerular ib puag ncig, vim tias podocytes tuaj yeem dhau los ua lub hom phiaj thiab qhov chaw ntawm kev raug mob, pab txhawb kev ua kom muaj zog hauv zos thiab nthuav tawm lawv tus kheej kev puas tsuaj [44, 45].

Table 1 Cov ntsiab lus ntawm (muaj peev xwm thiab lees paub) podocyte lub cev tiv thaiv kab mob

Cov ntsiab lus ntawm lub cev tiv thaiv kab mob tseem ceeb ntawm podocytes tau sau tseg hauv Table 1.

Podocyte thiab complement system

Qhov kev sib txuas ntxiv, tau piav qhia raws li ib feem ntawm lub cev tiv thaiv kab mob hauv lub cev, sawv cev qhov tseeb ntawm kev ua haujlwm txuas ntawm lub cev thiab kev tiv thaiv kab mob. Nws muaj ntau dua 30 plasma lossis membrane-anchored proteins thiab regulators uas ua lub luag haujlwm hauv o, opsonization, thiab lysis ntawm cov kab mob, tshem tawm cov hlwb apoptotic, thiab kev txhim kho ntawm ob leeg innate thiab adaptive tiv thaiv [46-48]. Nws tuaj yeem qhib tau los ntawm peb txoj kev sib txawv, cov classical, lectin, thiab lwm txoj hauv kev [49, 50], uas yog nruj tswj hwm los ntawm ntau cov khoom ntxiv, xws li cov membrane-bound proteins CD46, CD55, thiab CD59 thiab soluble CFH. , txhawm rau tiv thaiv kev tsis sib haum xeeb ntxiv hyperactivation [51]. Tag nrho peb txoj hauv kev ua rau muaj cov kab mob proteolytic uas ua rau muaj kev sib koom ua ke nrog kev sib koom ua ke tom qab membrane nres complex (MAC) hauv lub cell plasma membrane. Thaum muab tso rau hauv lub lipid bilayer, MAC tsim ib qho pore ruaj khov nrog ~ 10 nm txoj kab uas hla tsim ntau lub teeb liab intracellular, uas tau pom los ntawm ob qho tib si hauv vivo thiab hauv vitro qauv raws li tau piav qhia hauv Table 2 [52].

cistanche ntxiv cov txiaj ntsig-yuav ua li cas ntxiv dag zog rau lub cev

Sublytic cuam tshuam ntawm kev ua kom tiav ntawm podocyte

Mechanical, oxidative, thiab immunologic stress tuaj yeem ua rau podocyte puas thiab tom qab ntawd cuam tshuam rau kev ncaj ncees ntawm glomerular barrier. Ua kom tiav nrog sublytic MAC tsim ntawm podocytes yog ib qho piv txwv ntawm kev ntxhov siab hauv kev tiv thaiv kab mob, uas tuaj yeem ua rau txoj hauv kev hauv qab no suav nrog cov protein kinases, lipid metabolism, cytokine tsim, ROS tiam, kev loj hlob ntawm cov teeb liab transduction, endoplasmic reticulum stress, thiab ubiquitin-proteasome system, thaum kawg. ua rau muaj kev cuam tshuam ntawm podocyte actin cytoskeleton thiab tom qab cell detachment [53]. Ntau qhov kev nthuav dav, cov pov thawj qhia tau hais tias ib qho nyiaj sublytic ntawm MAC ntawm lub ntsej muag podocyte tuaj yeem ua rau cov calcium nkag los ntawm cov membrane pore, nrog rau cov calcium tso tawm los ntawm cov khoom ntim hauv lub cev, nws thiaj li ua rau cov calcium ntau ntxiv uas tuaj yeem ua rau ntau txoj hauv kev, xws li cov protein. kinase signaling, thiab tshwj xeeb tshaj yog protein kinases C (PKC) lub luag hauj lwm rau daim nyias nyias vesiculation thiab internalization ntawm MAC channels [52, 54-57], raws li qhia los ntawm kev txo MAC endocytosis los ntawm inhibiting PKC txoj kev [58]. Nws paub zoo tias Ca2+ kev taw qhia hauv podocytes noj qab haus huv feem ntau yog kho los ntawm angiotensin II thiab TRPC5 thiab 6 (nonselective cationic channels, downstream of angiotensin II signaling) [59]; nthuav, TRPC6 tuaj yeem ua lub luag haujlwm dual, raws li nws tau pom tias kev ua kom mob hnyav ntawm cov channel no tuaj yeem tiv thaiv podocytes los ntawm kev raug mob ntxiv, thaum nce-ntawm-function hloov pauv / mob ntev tuaj yeem cuam tshuam rau SD thiab / lossis cov txheej txheem ko taw. morphology ua rau cov kab mob glomerular, xws li FSGS [60].

Table 2 Kev taw qhia txoj hauv kev qhib los ntawm MAC (hloov los ntawm Takano li al. (2013). Seminars in Nephrology. Reference [52]

induce transactivation ntawm receptor tyrosine kinases ntawm plasma daim nyias nyias ntawm kab lis kev cai podocytes, ua rau ua kom lub Ras-extracellular signal-regulated kinase (ERK) txoj kev thiab phospholipase C- 1. Transactivated receptor tyrosine kinases tuaj yeem ua lub luag haujlwm hauv kev sib sau ua ke ntawm cov protein thiab / lossis kev ua kom muaj zog, ua kom muaj kev ua haujlwm ntawm cov dej ntws hauv qab, txawm tias nyob ntawm nws tus kheej los ntawm kev nce cytosolic calcium ntau ntau [54, 61]. Lwm txoj hauv kev qhib los ntawm MAC tsim ntawm podocyte nto koom nrog arachidonic acid (AA) tso tawm los ntawm cytosolic phospholipase A2- (cPLA2), inducing AA metabolism rau prostanoids, raws li tau piav los ntawm Cybulsky li al. [62]. Eicosanoids tuaj yeem ua lub luag haujlwm hauv kev sib koom ua ke ntawm kev raug mob podocyte, raws li kev txhawb nqa los ntawm kev sim ua qauv ntawm membranous nephropathy. Txawm hais tias muaj tseeb cov txheej txheem ntawm kev puas tsuaj glomerular tseem tsis tau paub meej, cytotoxic qhov tshwm sim ntawm cPLA2 kev ua kom muaj xws li tso tawm cov roj fatty acids dawb thiab lysophospholipids, nrog rau cov ions influx, uas tuaj yeem cuam tshuam rau lub zog ntawm lub tshuab [63].

ROS ntau lawm kuj tau piav nyob rau hauv podocytes raug rau sublytic npaum li cas ntawm MAC; ob qho tib si kab lis kev cai thiab hauv vivo podocytes nthuav qhia cov khoom ntawm NADPH oxidase, ib qho enzyme nyuaj tuaj yeem txo cov pa oxygen molecular mus rau superoxide anion, uas yog ntxiv metabolized rau lwm yam ROS [52]. Lipid peroxidation thiab kev hloov pauv hauv podocyte membrane muaj pes tsawg leeg, nrog rau hauv GBM cov khoom, tau raug tshaj tawm tias yog qhov tshwm sim ntawm ROS ntau lawm. Tsis tas li ntawd, inhibition ntawm ROS thiab / lossis lipid peroxidation ua rau txo qis proteinuria hauv cov tsiaj qauv ntawm membranous nephropathy, qhia lawv lub luag haujlwm pathogenic hauv glomerular puas [64]. Endoplasmic reticulum (ER) kev ntxhov siab nrog rau kev sib sau ntawm misfolded proteins thiab kev nce ntxiv ntawm ubiquitin-proteasome system tau raug tshaj tawm tias yog ib qho lus teb ntxiv rau kev raug mob ntxiv, raws li qhov muaj peev xwm tiv thaiv cov lus teb ntawm podocytes mus txuas ntxiv kev tawm tsam [65]. Sublytic MAC deposition ntawm podocytes kuj tuaj yeem ua rau DNA puas tsuaj, ob qho tib si hauv vitro thiab hauv vivo qauv, raws li pom los ntawm Pippin li al. [66]. Cov kws sau ntawv kuj tau piav qhia tias sublytic MAC-induced podocyte raug mob tau cuam tshuam nrog kev nce hauv cov kab mob tshwj xeeb ntawm cov noob caj noob ces, suav nrog p53, p21, kev loj hlob-ntxuav DNA puas tsuaj-45, thiab checkpoint kinase{11}} thiab 2 , ua rau lub voj voog ntawm tes ntes thiab podocyte kev loj hlob suppression. Qhov no tuaj yeem piav qhia yog vim li cas qhov kev loj hlob ntawm podocyte yog txwv tom qab kev tiv thaiv kab mob sib kis.

Qhov tshwm sim ntawm kev ua kom tiav ntawm podocyte zog metabolism

Cov teebmeem ntawm kev ua kom ntxiv rau ntawm lub tshuab hluav taws xob podocyte tsis nkag siab tag nrho. Brinkkoetter et al. pom tau hais tias podocyte metabolism yog txawv me ntsis ntawm lwm hom hlwb, raws li nws feem ntau tso siab rau anaerobic glycolysis thiab hloov cov piam thaj rau lactate [67]. Ntxiv rau qhov nthuav dav, cov kws sau ntawv tau pom qhov tsawg dua mitochondrial ntom ntawm ib cheeb tsam ntawm tes, piv rau lwm hom ntawm lub raum hlwb (piv txwv li, lub raum tubular hlwb). Tsis tas li ntawd, glomeruli stained rau mitochondrial enzyme superoxide dismutase 2 (SOD2) thiab glycolytic enzyme pyruvate kinase M2 (PKM2) tau lees paub qhov perinuclear localization ntawm mitochondria (thiab lawv yuav luag tsis ua tiav hauv cov txheej txheem thib ob thiab theem nrab), thaum PKM2 tau tawm tswv yim tawm. raws li ib tug loj compartment ntawm anaerobic glycolysis. Lawv kuj siv Tfam (mitochondrial transcription factor A) knockout nas los ua kom pom tias poob ntawm mitochondrial transcription thiab tsis muaj oxidative phosphorylation machinery tsis ua rau cov kab mob podocyte. Tsis tas li ntawd, ib ntus knockdown ntawm Tfam nyob rau hauv tib neeg podocytes txo qis mitochondrial ua pa, thaum anaerobic glycolysis tau nce ntxiv ua rau muaj kev ua haujlwm ntawm podocyte. Nws tau pom tias sublytic complement-mediated raug mob induces txo ntawm intracellular ATP, ntxiv rau reversible cuam tshuam ntawm actin stress fibers thiab focal adhesions, feem ntau yog vim dephosphorylation (es tsis txhob degradation) ntawm focal contact proteins, raws li tau piav los ntawm Topham li al. siv tus qauv hauv vitro ntawm nas podocytes [68]; Txawm li cas los xij, cov txheej txheem meej yuav tsum tau qhia meej. Tsis tas li ntawd, kev ua kom muaj zog ntxiv ntawm podocytes tuaj yeem ua rau nephrin dissociation los ntawm actin cytoskeleton nrog kev cuam tshuam ntawm lub diaphragm, GFB kev puas tsuaj, thiab tom qab pib ntawm proteinuria, raws li tau hais los ntawm Heymann nephritis (HN) qauv [54, 61].

Ua kom tiav qhov kev raug mob thiab cov lus teb podocyte

Podocytes cia siab rau ntau lub tswv yim hloov kho kom txo tau qhov kev raug mob ntxiv-kev kho mob. Autophagy, ib qho kev tiv thaiv zoo heev ntawm lysosome-mediated degradation ntawm cov organelles puas los yog cov proteins uas tsis ua haujlwm, yog txhim kho tom qab sublytic ntxiv kev puas tsuaj hauv nas podocytes, thaum nws inhibition ua kom ntxiv dag zog rau cov cell raug mob [69]. Liu et al. tshawb xyuas lub luag haujlwm ntawm autophagy hauv PMN, piv cov podocytes los ntawm PMN cov neeg mob mus rau kab lis kev cai nas podocytes raug rau sublytic ntxiv kev ua ub no, thiab lawv pom muaj kev cuam tshuam autophagy hauv podocytes los ntawm PMN cov neeg mob, tus cwj pwm los ntawm intracellular tsub zuj zuj ntawm p62 (ib qho cim ntawm impaired autophagy) thiab nce ntxiv. autophagic vacuoles [70]. Podocyte-derived VEGF kuj tseem muaj kev ua haujlwm bivalent, raws li nws tau piav qhia tias nws cov lus tshaj tawm tuaj yeem ua rau lub cev tsis muaj zog, thaum nws inhibition cuam tshuam nrog GFB cuam tshuam, proteinuria, thiab muaj peev xwm txhim kho thrombotic microangiopathy zoo li [71]. Cov txheej txheem putative yog tias, nyob rau hauv ib txwm muaj, VEGF teeb liab tuaj yeem tswj hwm kev ua haujlwm ntxiv ntawm podocytes thiab tiv thaiv lawv los ntawm kev sib koom ua ke ntawm kev raug mob los ntawm kev tsim cov CFH hauv zos, thaum nws inhibition yuav ua rau txo qis ntawm CFH, thiab podocytes yuav ua rau muaj kev cuam tshuam ntau dua. raug mob.

Tsis ntev los no, cov txheej txheem nthuav dav tshiab tau piav qhia los tiv thaiv podocytes los ntawm kev raug mob, raws li qhia los ntawm Medica li al. siv cov qauv kev coj noj coj ua ntawm glomerular endothelial cells thiab podocytes. Tshwj xeeb, lawv tau pom tias cov hlwv extracellular muab tau los ntawm cov endothelial progenitor hlwb thiab koom nrog intercellular crosstalk (los ntawm kev hloov cov proteins, lipids, thiab genetic khoom) muaj peev xwm tiv thaiv ob glomerular endothelial hlwb thiab podocytes los ntawm ntxiv (C5a)- thiab cytokine-mediated. raug mob [72]. Tshwj xeeb, lawv tau pom tias ua ntej stimulation ntawm endothelial hlwb nrog extracellular vesicles tiv thaiv podocyte apoptosis thiab GFB cuam tshuam, thiab qhov kev tiv thaiv no tuaj yeem yog qhov tseem ceeb ntawm RNA hloov ntawm cov hlwv extracellular mus rau puas hlwb endothelial thiab podocytes. Txawm hais tias muaj kev soj ntsuam nruj ntawm cov txheej txheem ntxiv, suav nrog kev ua haujlwm ntawm cov kuab tshuaj thiab cov txheej txheem membrane-bound, ua ke nrog cov txheej txheem tiv thaiv yav dhau los tau piav qhia kom dim ntawm kev raug mob, kev ua kom tsis muaj zog ntxiv tuaj yeem tshaj li cov txheej txheem tswj hwm, ua rau cov ntaub so ntswg raug mob, raws li qhia hauv ntau yam kab mob. suav nrog glomerulonephritis [73], hemolytic uremic syndrome (HUS) [74], sepsis [75], systemic lupus erythematosus [76], rheumatoid mob caj dab [77], kev hloov pauv hauv nruab nrog cev [78], thiab muaj hnub nyoog ntsig txog macular degeneration [79] .

Summary thiab xaus

cistanche cog-nce kev tiv thaiv kab mob

Podocytes ua lub luag haujlwm tseem ceeb hauv kev ua kom cov glomerular homeostasis. Tau ntau xyoo, cov ntaub ntawv loj hlob tau qhia txog ntau yam kev ua haujlwm lom neeg ntawm cov kab mob pericytes zoo li epithelial, uas muaj ntau tshaj li qhov txhawb nqa ntawm GFB [1, 80–82]. Ntau tus kws sau ntawv tau piav qhia lawv tias yog "cov kab mob tiv thaiv kab mob podocytes," txhawm rau txheeb xyuas lawv cov khoom raws li ob qho tib si hauv lub cev thiab hloov lub cev tiv thaiv kab mob [10, 13, 15]. Kev nkag siab txog lawv txoj kev biology yog qhov tseem ceeb los daws cov kab mob pathogenic ntawm ntau cov kab mob glomerular, qhov twg podocyte raug mob sawv cev rau tus lej sib txawv.

Lub luag haujlwm ntawm cov txheej txheem ntxiv hauv kev raug mob podocyte kuj tau raug soj ntsuam hauv ntau lub raum mob, xws li membranous nephropathy, lupus nephritis, HUS, FSGS, thiab ntau ntxiv [45, 83–90]. Cov teebmeem ntawm kev ua kom muaj zog ntxiv ntawm podocytes tuaj yeem sib txawv raws li kab mob pathophysiology, nrog rau raws li qhov pib tshwm sim, uas tuaj yeem ua rau muaj kev cuam tshuam lytic piv rau cov teebmeem sub-lytic. Interestingly, podocytes tau tsim ntau lub tswv yim tiv thaiv kom dim ntawm kev tawm tsam ntxiv, xws li autophagy, internalization mechanisms zoo li endocytosis, thiab kev qhia txog kev tswj hwm, thiab qhov sib npaug ntawm kev raug mob thiab kev tiv thaiv mechanisms kawg tuaj yeem txiav txim siab txoj hmoo ntawm podocyte cell [65, 69. , 91] ib. Cov kev tshawb fawb yav tom ntej, ob qho tib si hauv vitro thiab hauv vivo, yuav tsum tau nkag siab zoo txog lub luag haujlwm ntawm kev ua kom muaj zog ntxiv hauv podocytopathies thiab lub laj thawj rau kev siv cov tshuaj tiv thaiv ntxiv hauv cov xwm txheej uas cov txheej txheem ntxiv tshwm sim ua tus tsav tsheb tseem ceeb ntawm tus kab mob.

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