Kev mob raum mob raum mob raum kev loj hlob: Lub luag haujlwm ntawm Nrf2
Mar 16, 2022
Hu rau: Audrey Hu Whatsapp / hp: 0086 13880143964 Email:audrey.hu@wecistanche.com
Peter Stenvinkel1, Glenn M. Chertow2, Prasad Devarajan3, Adeera Levin4, Sharon P. Andreoli5, Sripal Bangalore6thiab Bradley A. Warady7
1 Department of Renal Medicine M99, Karolinska University Tsev Kho Mob ntawm Huddinge, Karolinska Institutet, Stockholm, Sweden;
2Division of Nephrology, Stanford University, Stanford, California, USA;
3Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA;
4Department of Medicine, University of British Columbia, Vancouver, Canada;
5Department of Pediatrics, Indiana University School of Medicine, Indiana University, Indianapolis, Indiana, USA;
6Division of Cardiology, New York University, New York, New York, Tebchaws USA; thiab
7Division of Pediatric Nephrology, Children's Mercy Kansas City, Kansas City, Missouri, USA
Txawm tias tsis ntev los no kev nce qib hauv kev tswj hwm ntawmmob raum mob(CKD), morbidity thiab tuag tus nqi ntawm cov neeg mob no tseem siab. Txawm hais tias qhov kev raug mob siab-kev kho mob yog ib qho kev pom zoo ntawm cov kab mob kev loj hlob hauv CKD, cov ntaub ntawv tawm tshiab qhia tau hais tias qhov nruab nrab phenotype cuam tshuam nrog kev mob ntev, oxidative stress, hypoxia, senescence, thiab mitochondrial dysfunction plays lub luag haujlwm tseem ceeb hauv etiology, kev loj hlob, thiab pathophysiology. ntawm CKD. Ntau yam ntawm cov xwm txheej txhawb kev mob ntev hauv CKD, suav nrog kev ntxhov siab oxidative thiab kev siv cov tshuaj proinflammatory phenotype los ntawm cov neeg nyob hauv lub raum hlwb. Kev tswj hwm ntawm pro-inflammatory thiab anti-inflammatory yam cuam tshuam los ntawm NF-κB- thiab nuclear factor, erythroid 2 nyiam 2 (nrf 2) – mediated gene transcription, ntsig txog, plays lub luag haujlwm tseem ceeb hauv glomerular thiab tubular cell teb rau lub raum raug mob. Kev mob ntev ua rau muaj kev poob qis hauv glomerular filtration rate (GFR) hauv CKD. Whereas lub luag hauj lwm ntawm mob o nyob rau hauv cov ntshav qab zibmob raum(DKD) tau raug qhia kom meej, tsis muaj pov thawj tseem ceeb uas qhia tau tias tsis muaj kev kho mob ua rau mob fibrosis thiab qhov kawg ntawm qhov kawg.mob raum(ESKD) nyob rau hauv ntau lwm yam kab mob, xws li Alport syndrome, autosomal-dominant polycysticmob raum(ADPKD), IgA nephropathy (IgAN), thiab focal segmental glomerulosclerosis (FSGS). Hauv qhov kev tshuaj xyuas no, peb tsom kom qhia meej txog cov txheej txheem ntawm kev mob ntev hauv cov kab mob pathophysiology thiab kab mob kev loj hlob thoob plaws lub spectrum.kab mob raum, nrog tsom ntsoov raunrf 2.
KEYWORDS:mob mob; mob raum mob; mitochondrial tsis ua haujlwm;nrf 2; oxidative kev nyuaj siab; cov kab mob hauv lub raum
Kev kho mob ntawm mob raum mob: cistanche extract
Kev raug mob siab-mediated yog ib qho kev pom zoo rau cov qauv kev puas tsuaj hauv CKD.1, 2, 3 Cov kev kho mob uas txo qis intraglomerular siab (angiotensin-hloov enzyme inhibitors lossis angiotensin-receptor blockers) feem ntau siv rau kev kho mob ntawm CKD thiab muaj kev cuam tshuam zoo ib yam. ntawm pathogenic mechanisms cuam tshuam nrog ntshav siab thiab proteinuria. Txawm li cas los xij, cov teebmeem ntawm angiotensin-hloov pauv enzyme inhibitors thiab angiotensin-receptor blockers ntawm cov txiaj ntsig ntawm kev kho mob, suav nrog kev ua kom qeeb ntawm lub raum tsis ua haujlwm thiab txo qhov tshwm sim ntawm ESKD, yog ntau me ntsis.4, 5, 6, 7, 8, 9 Txhawm rau txo qis, ntes, lossis thim rov qab CKD kev nce qib, nephrologists yuav tsum tau tsom rau cov txheej txheem pathogenetic uas tsis yog hloov pauv glomerular hemodynamics.10,11
Lub luag haujlwm ntawm Nrf2 rau Kev Mob Ntsws Hauv Kab Mob Raum Kab Mob
Kev mob o thiab mitochondrial dysfunction tau nce zuj zus lees paub tias ua rau lub raum fibrosis thiab ESKD.12,13 Tsis hais txog ntawm CKD etiology, mob o tuaj yeem tshwm sim raws li qhov ua rau thiab qhov tshwm sim ntawm glomerular thiab tubulointerstitial pathology.12,14, 15, 16, 17 Nyob rau hauv ntau hom CKD, proteinuria yog ib tug zoo-paub kwv yees ntawm tus kab mob kev loj hlob18 thiab cov neeg mob uas asymptomatic proteinuria pom cov qis-qib o txuas mus rau endothelial dysfunction.19 Whereas proteinuria pab rau lub pathology ntawm CKD los ntawm inducing adversely hloov nyob rau hauv glomerular muaj nuj nqi. , xws li tsis muaj kev xaiv ntawm glomerular barrier, glomerular hypertrophy, 20 thiab ncaj qha kev puas tsuaj rau tubule epithelial hlwb, nws kuj ua li ntawd los ntawm kev txhawb o.21,22.
Cov txiaj ntsig tau los ntawm kev nthuav qhia txoj hauv kev tsom xam ntawm cov noob caj noob ces txuas rau kwv yees GFR hauv 157 European cov neeg mob nrog 9 hom sib txawv ntawm CKD qhia tias qhov mob thiab cov metabolism yog 2 txoj hauv kev tseem ceeb hauv cov kab mob ua rau CKD kev vam meej (Daim duab 1).23 Steady-state. mRNA nthuav qhia cov ntaub ntawv thoob plaws ntau yam etiologies ntawm CKD tau qhia txog kev tswj hwm ntawm cov noob caj noob ces, suav nrog tib neeg leukocyte antigen isoforms, Tus xov tooj zoo li 1 thiab 3, thiab NF-κB1.23 Qhov kev tshuaj ntsuam no tau nthuav tawm cov noob caj noob ces thiab cov protein sib cuam tshuam thiab txhais cov tswv yim tshiab, uas ua rau muaj kev puas tsuaj lom neeg thoob plaws ntau yamkab mob raum, suav nrog cov kab mob hauv qab daus nyias nyias, FSGS, membranous nephropathy, cov kab mob hloov pauv tsawg, mob ntshav qab zib nephropathy, hypertensive nephropathy, IgAN, thiab lupus nephritis.23 Tseem ceeb heev, qhov cuam tshuam ntawm nuclear, erythroid 2 zoo li 2 (Nrf2) anti-inflammatory pathway, tau tham txog qhov nthuav dav tom qab. nyob rau hauv qhov kev tshuaj xyuas no, tau txais kev pabcuam raws li lub hub ntawm 2 pawg ntawm inflammatory thiab metabolic pathways qhib nyob rau hauv ntau yam etiologies ntawm CKD, tawm tswv yim ib tug txheej txheem ntawm o thiab metabolism regulation.23 Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog los tham txog lub luag hauj lwm ntawm o thiabnrf 2nyob rau hauv kev loj hlob ntawm CKD ntawm txawv etiologies.
Daim duab 1. Inflammation and metabolism in CKD progression.23 Inflammation and metabolism is 2 main pathways lead to CKD progression, nrog raunrf 2ua haujlwm raws li lub hub. Luam tawm nrog kev tso cai los ntawm American Society of Nephrology, los ntawm: Integrative biology txheeb xyuas cov kev sib txuas lus sib txuas hauv CKD, Martini S li al., Vol 25, Issue 11, copyright 2014; kev tso cai xa tawm los ntawm Copyright Clearance Center, Inc. CKD,mob raum mob.
Kev mob ntsws ntev hauv Kev Txhim Kho ntawm CKD
Mob ntsws thiab Oxidative Stress
Kev mob qis qis tsis tu ncua24 thiab oxidative kev nyuaj siab (piv txwv li, qhov nce ntawm cov pa oxygen reactive [ROS]) 25 yog cov koom tes hauv kev ua txhaum cai thiab cov ntsiab lus ntawm uremic phenotype uas txhawb kev laus ntxov ntxov26 thiab lub raum fibrosis.27,28 Kev mob plab thiab oxidative kev nyuaj siab koom nrog. ib lub voj kev tawm tswv yim zoo, uas txhua qhov ua kom muaj zog rau lwm tus.29 Oxidative stress induces o los ntawm activating NF-κB nrog rau cov cytokines tom ntej (piv txwv li, interleukin [IL]-1 , IL-1 , qog necrosis factor [TNF], IL-6) 30, 31, 32 cuam tshuam nrog kev poob qis hauv kwv yees li GFR.33 Cov ntaub ntawv muab los ntawm Kev Tshawb Fawb Txog Lub Raum Tsis Txaus Siab Kev Tshawb Fawb tau qhia tias kev ncig IL-6 thiab TNF receptor 2 yog cuam tshuam nrog qhov xwm txheej CKD34 thiab TNF receptor 2 yog ntawm nws tus kheej cuam tshuam nrog rau lub raum poob sai dua hauv CKD.35
Cov kab mob hauv lub raum nyob hauv qhov mob ntev
CKD kev loj hlob tshwm sim feem ntau yog los ntawm lub raum fibrosis, txheej txheem uas ua kom muaj myofibroblasts yog lub ntsiab collagen-tsim hlwb.36, 37, 38 Collagen, feem ntau fibrillar collagens I thiab III, yog ib qho tseem ceeb contributor rau fibrosis-induced cellular poob hauv CKD.39. Ntawm ntau txoj hauv kev uas txo cov kev sim fibrosis, xws li kev tsom mus rau kev hloov pauv, kev taw qhia, thiab txoj hauv kev loj hlob, thiab cov kev hloov pauv hauv epigenetic, xws li microRNAs, cov kev tiv thaiv kab mob tau txais kev saib xyuas tsis ntev los no.11 Raws li tau sau tseg yav dhau los, kev mob ntev yog txuas nrog rau ob qho tib si CKD pib thiab kev loj hlob.40, 41, 42, 43 Nyob rau hauv sib piv rau mob mob, uas yog ib tug natural tiv thaiv kab mob rau lub raum raug mob44,45 uas plays ib tug luag hauj lwm nyob rau hauv lub raum kho cov ntaub so ntswg tom qab raug rau teeb meem stimuli, mob o yog ib tug maladaptive teb. uas tshwm sim los ntawm kev ua kom tsis tu ncua ntawm pro-inflammatory signaling pathways.2,3,17,44,46,47
Txawm hais tias mob hnyav yog cim los ntawm kev nkag mus rau cov qe ntshav dawb, 48 mob ntev yog qhov tshwm sim los ntawm kev ua kom cov kab mob hauv lub raum uas pom muaj cov tshuaj tiv thaiv kab mob proinflammatory phenotype.49, 50, 51, 52, 53 Ua kom cov neeg nyob hauv lub raum, suav nrog cov hlwb mesangial, cov hlwb endothelial. , tubular epithelial hlwb, thiab podocytes, ua rau tsim cov tshuaj proinflammatory chemokines lub luag hauj lwm rau perpetuating lub voj voog ntawm cov mob ntev uas nws thiaj li ua rau lub raum fibrosis thiab poob raum tsis ua hauj lwm (Daim duab 2).50,53,54.
Daim duab 2. Kev ua kom lub raum nyob hauv lub raum ua rau muaj qhov mob ntev hauv CKD.53 Cov kab mob hauv lub raum proliferate thiab tsim cov tshuaj proinflammatory chemokines lub luag hauj lwm rau perpetuating lub voj voog ntawm mob mus ntev ua rau lub raum fibrosis. Hloov kho los ntawm kev tso cai los ntawm Springer Nature. Nat Rev Immunol. Lub cev tiv thaiv kab mob thiabmob raum: Cov ntsiab lus yooj yim thiab qhov cuam tshuam rau kev kho mob. Kurts C et al. Copyright 2013. IFN-ɑ, interferon alpha; IL-6, interleukin 6; TNF, qog necrosis factor.
Nce qib ntawm inflammatory cytokines thiab deposition ntawm extracellular matrix (ECM) ua rau tubulointerstitial fibrosis, mesangial expansion, thiab ib tug tom qab poob rau hauv GFR.55 Ntawm kev ua kom, mesangial hlwb tso chemokines thiab cytokines, uas ua nyob rau hauv lub zos mesangial hlwb, lwm yam glomerular hlwb. thiab leukocytes. Nyob rau hauv lub xub ntiag ntawm mob mesangial cell activation, ECM expansion nyob rau hauv lub interstitial qhov chaw ua rau interstitial fibrosis, uas ua rau glomerulosclerosis.50 Nyob rau hauv lub classic 5/6 nephrectomy CKD qauv, NF-κB yog activated thiab transforming loj hlob yam beta (TGF- ) yog. up-regulated.56 NF-κB yog ib tug regulator ntawm proinflammatory genes uas orchestrates thiab tsim pua pua ntawm inflammatory cytokines thiab mediators.36,57,58 Ua kom TGF- ua rau mob fibrosis.2 Podocytes qhia TGF- tom qab pib ntawm proteinuria,59 uas tom qab ntawd txhawb kev hloov pauv ntawm epithelial thiab mesangial hlwb mus rau hauv fibroblasts thiab myofibroblasts.2 TGF- kuj ua rau podocytes tsim ECM proteins uas accumulates nyob rau hauv lub tubulointerstitium.59 TGF- yog synthesized los ntawm tubular epithelial hlwb thiab myofibroblasts nyob rau hauv ntau theem ntawm lub raum. fibrosis.60
Proinflammatory Mediators hauv CKD
Glomerular kev puas tsuaj tshwm sim los ntawm qhov tsis ua kom tshem tawm cov teeb meem proinflammatory stimuli nyob rau hauv glomerular hlwb los yog caj ces hloov mus rau ib tug proinflammatory xeev.36,44,50 yam uas yuav ua rau ib tug proinflammatory tubular cell teb muaj xws li tso tawm cytokines, to ntawm albumin thiab ntxiv proteins, hypoxia tshwm sim los ntawm endothelial dysfunction, thiab ncaj qha raug mob vim yog immunologic, kis, tshuaj lom, metabolic, los yog insults.17 Tsis tas li ntawd, senescence ntawm tubular hlwb thiab podocytes txhawb ib tug senescence-koom nrog secretory phenotype nrog nce lub zos secretion ntawm lub raum kev sib txuas ntawm cov proteins. muaj nuj nqi rau cov ntaub so ntswg o.61 raum hypoxia/ischemia pab txhawb kev loj hlob ntawmmob raumlos ntawm ob qho tib si o thiab oxidative kev nyuaj siab.62 Txij li thaumnrf 2deficiency ua rau kom muaj kev cuam tshuam rau ischemia-reperfusion-induced raum raug mob, 63 nce-txoj cai ntawmnrf 2tuaj yeem tiv thaiv lub raum tsis zoo tiv thaiv kev rov ua dua ntawm ischemia thaum muaj xwm txheej tsis zoo.
Tubular cell activation txhawb kev puas tsuaj ntxiv los ntawm interstitial leukocyte recruitment thiab ua kom, tso tawm ntawm profibrotic kev loj hlob yam tseem ceeb (xws li, platelet-derived kev loj hlob yam, connective cov ntaub so ntswg loj hlob, thiab TGF-), thiab stimulation ntawm myofibroblast tsub zuj zuj thiab ua kom ua rau interstitial collagen deposition thiab fibrosis.17,64 Cov ntau yam inflammatory mediators koom rau hauv cov txheej txheem nyuaj ntawm kev mob o, kho, fibrosis, thiab poob ntawm lub raum kev ua haujlwm tau sau tseg nyob rau hauv daim duab 3.36 Genetic thiab epigenetic yam tseem ceeb muaj zog determinants ntawm o nyob rau hauv CKD.23,65 Ib qho kev ntsuam xyuas dav. qhia tias genotype muaj feem cuam tshuam nrog qhov muaj qhov mob hauv cov neeg mob nrog CKD, raws li tau hais los ntawm kev nthuav dav ntawm qib siab CRP, qhov phenotypic nta tsis tshua paub qhov txawv ntawm cov neeg mob o ntawm cov tsis muaj.66
Daim duab 3. Cov neeg kho mob ntawm cov mob ntevmob raum.36 Ntau yam inflammatory mediators koom nrog cov txheej txheem nyuaj uas ua rau lub raum tsis ua haujlwm. Hloov nrog kev tso cai los ntawm Elsevier. Keeb kwm luam tawm hauv Eur J Pharmacol. Vol 820. Lv W et al. Kev mob plab thiab lub raum fibrosis: kev txhim kho tsis ntev los no ntawm cov cim tseem ceeb ntawm cov khoom siv raws li lub hom phiaj kho mob. Nplooj 65 txog 76. Copyright 2018, Elsevier. ECM, extracellular matrix; EMT, epithelial-mesenchymal transdifferentiation; GFR, glomerular pom tus nqi; ROS, reactive oxygen hom; TNF, qog necrosis yam; TGF-, transforming loj hlob yam beta; TWEAK, TNF zoo li qaug zog inducer ntawm apoptosis.
Proinflammatory Role ntawm NF-κB hauv CKD
Hauv CKD, kev ua kom ROS-tsim enzymes (piv txwv li, nicotinamide adenine dinucleotide phosphate oxidase thiab xanthine oxidase) pab txhawb oxidative kev nyuaj siab nyob rau hauv lub raum.67 Oxidative stress triggers activation ntawm NF-κB, pab txhawb inflammatory teb. NF-κB orchestrates thiab txhawb kev tsim tawm ntawm ntau yam inflammatory cytokines thiab mediators.2,36,57,58 Cytokines tsim los ntawm ntau lub raum hlwb nrhiav cov macrophages rau cov ntaub so ntswg puas, uas ua rau muaj zog ntau lawm ntawm proinflammatory yam thiab glomerulosclerosis.2 ,3
Anti-inflammatory Lub luag haujlwm ntawm Nrf2 hauv CKD
nrf 2sawv cev rau qhov tseem ceeb ntawm cov cellular uas hloov zuj zus raws li kev tiv thaiv oxidative kev nyuaj siab thaum cov kab mob ntau pua lab xyoo dhau los pib tshawb txog lub ntiaj teb saum cov dej hiav txwv thiab raug cov pa oxygen.68, 69, 70, 71 Ib tug tswv cuab ntawm tsev neeg bZIP ntawm kev sau ntawv. yam tseem ceeb-tshwj xeeb hauv CNC subfamily-Nrf2 muaj 7 qhov chaw ua haujlwm (Neh1 txog Neh7) nrog ntau yam haujlwm. Nrf2 heterodimerizes nrog sMaf proteins K, G, thiab F nyob rau hauv lub nucleus, uas pab txhawb kev paub txog kev txhim kho kab ke hu ua cov tshuaj tiv thaiv antioxidant uas pom nyob rau hauv cov cheeb tsam tswj hwm ntawm ntau tshaj 250 genes.3,70,72, 73, 74
Lub luag haujlwm ntawm Nrf2 hauv Kev Tswj Kab Mob
Nrf2 tiv thaiv lub raum hlwb thiab lwm cov ntaub so ntswg los ntawm upregulating ib tug array ntawm noob thiab thiaj li attenuating zus tau tej cov proinflammatory cytokines.15 Molecules uas muaj ntau ntau los ntawm Nrf2 muaj xws li catalase, superoxide dismutase, glutathione peroxidase, heme oxygenase -1, txo nicotinamide. adenine dinucleotide phosphate quinone oxidoreductase, thiab glutamate-cysteine ligase.15 Ib qho kev sib npaug ntawm cov protein synthesis thiab proteasomal degradation yog yuav tsum tau kom tswj cov intracellular concentration ntawm Nrf2 nyob rau theem qis.74 Lub cytosolic inhibitor Keap1 khi raunrf 2hauv cytoplasm.67,71,75
Raws li ib txwm muaj, Keap1 lub hom phiajnrf 2rau degradation los ntawm lub ubiquitin-proteasome system (Ntxiv daim duab S1).55,76 Nyob rau hauv tej yam kev mob ntawm oxidative kev nyuaj siab, electrophiles, thiab ROS hloov lub conformation ntawm Keap1 los ntawm kev tsim direct adducts nrog tshwj xeeb sensor cysteine residues.55,76 Xws li kev hloov kho hloov kev sib cuam tshuam. nruab nrab ntawm Keap1 thiab Nrf2, ua rau txo qis Nrf2 degradation hauv cov hlwb raug oxidative kev nyuaj siab. Nrf2 ces translocates mus rau hauv lub nucleus qhov twg nws activates lub transcription ntawm nws lub hom phiaj noob.
Nrf2 tseem ncaj qha cuam tshuam cov kev qhia ntawm proinflammatory NF-κB lub hom phiaj noob los ntawm kev khi rau lawv cov neeg txhawb nqa thiab inhibiting transcription.77 Cov kev sib txuas lus tseem ceeb ntawm Nrf2 thiab NF-κB txoj hauv kev tswj cov kev qhia ntawm ntau lub hom phiaj nqes hav.78 Yog li, Keap{{6 }}nrf 2system plays lub luag haujlwm tseem ceeb hauv kev daws teeb meem ntawm qhov mob los ntawm kev tawm tsam oxidative puas tsuaj thiab los ntawm inhibition ntawm proinflammatory NF-κB signaling.72,79,80
Cov ntaub ntawv pov thawj los ntawm tsiaj lub nceeg vaj qhia tias Nrf2-raws li cov tshuaj tiv thaiv antioxidant tau hloov zuj zus los tiv thaiv cov tsiaj thaum muaj xwm txheej hnyav.68 Inhibition ntawm Nrf2 kev ua txhawb kev ntxhov siab ua rau ntxov ntxov senescent phenotype81 thiab Nrf2 qhia txo qis nrog kev laus hauv nas.82 Raws li Kev tshawb pom tsis ntev los no qhia tau hais tias kev txo qis ntawm Nrf2 kev ua haujlwm txhawb nqa oxidative kev nyuaj siab thiab ua kom cov cellular senescence, nws tau pom tias cov tshuaj tsom mus raunrf 2signaling yuav suppress cellular senescence-koom nrog pathologies.83 Txij li thaum cov kev ua ntawmnrf 2Kev txo qis hauv Hutchinson-Gilford progeria syndrome, ib qho tsis tshua muaj mob ntawm kev laus ntxov ntxov, 84 thiab kev tshawb fawb ntawm Nrf2 knockout nas ntxhov siab los ntawm qhov chaw mus ncig pom tias muaj kev nce qib ntawm cov hnub nyoog cuam tshuam nrog cov metabolites, 85 Nrf2 tuaj yeem ua lub luag haujlwm tiv thaiv kev laus. Qhov tseeb, qhov mob qis qis tsis tu ncua (piv txwv li, "mob") thiab txo qis Nrf2 qhia yog cov yam ntxwv tseem ceeb ntawm CKD thiab lwm yam kab mob ntawm lub neej uas cuam tshuam nrog kev laus ntxov ntxov.68 raum fibrosis thiab epithelial-mesenchymal hloov pauv-ib txheej txheem uas sib txawv. cov hlwb epithelial tau txais kev hloov pauv phenotypic uas tsim cov matrix-producing fibroblasts thiab myofibroblasts-ua rau kev laus hauv lub raum86 thiab tej zaum yuav muaj kev cuam tshuam txog kev laus ntxov ntxov nyob rau hauv cov ntaub so ntswg.11 Raws li lwm yam kabmob ua rau muaj kev laus ntxov ntxov hauv lub raum. uremic milieu, kev loj hlob ntawmmob raumvim fibrosis thiab o feem ntau cuam tshuam nrog kev loj hlob ntawm ib qho uremic phenotype uas muaj vascular calcification, sarcopenia, osteoporosis, thiab lwm yam (Cov duab ntxiv S2).87.
Lub luag haujlwm ntawm Nrf2 rau Kev Mob Ntsws Hauv Kab Mob Raum Kab Mob
Lub luag haujlwm ntawm Nrf2 hauv raum Kab Mob
Cov txiaj ntsig los ntawm ntau qhov kev tshawb fawb qhia txog lub luag haujlwm tseem ceeb ntawm Nrf2 hauvmob raum.88, 89, 90, 91 Kev tshuaj xyuas tsis ntev los no ntawm 32 txoj kev tshawb fawb xaus lus tias thaumnrf 2kev qhia tsis tu ncua tsis tu ncua hauv CKD, NQO1, thiab HO-1 pom tias muaj kev hloov pauv ntau yam cuam tshuam nrog kev mob, comorbidities, thiab mob raum puas tsuaj.92 Jiang et al.69 tau pom tias cov qog nqaij hlav hauv lub raum los ntawm cov neeg mob DKD pom tau hais tias muaj ntau ntau. Glucose-induced ROS nyob rau hauv mesangial hlwb thiab ua kom covnrf 2thiab cov noob caj noob ces. Los ntawm immunohistochemistry, nws tau pom tias thaum Nrf2 tau qhia nyob rau hauv qis qis hauv ib txwm glomeruli, nws tau nce-tswj hauv glomeruli los ntawm cov neeg mob nrog DKD.69 Hauv qhov sib piv, kev tshuaj ntsuam ntawm 20 tus neeg mob ntawm hemodialysis, 20 tus neeg mob ntxiv nrog nondialysis-xav tau CKD. , thiab 11 tus neeg noj qab haus huv uas suav nrog kev ntsuam xyuas ntawm Nrf2 thiab NF-κB kev qhia nrog cov tshuaj tiv thaiv kab mob hauv lub sijhawm pom tau tias Nrf2 noob qhia tau txo qis thiab NF-κB qhia tau nce hauv peripheral ntshav mononuclear hlwb los ntawm cov neeg mob ntawm hemodialysis piv nrog cov neeg noj qab haus huv. thiab cov neeg mob uas tsis yog mob ntshav qab zib-yuav tsum tau CKD.93
Tsiaj thwmsim kuj qhia tau lub luag haujlwm tseem ceeb raunrf 2hauv kev tswj uremic o. Nrf2-knockout nas uas tswj hwm streptozotocin muaj ntau dua ROS ntau lawm thiab tshaj tawm oxidative DNA kev puas tsuaj thiab lub raum raug mob vs zoo li cov tsiaj qus hom.69 Impaired Nrf2 activation kuj tau txuam nrog raum fibrosis thiab kab mob kev loj hlob hauv tus qauv nas ntawm focal glomerulosclerosis.94 Raws li, impaired Nrf2 signaling thiab NF-κB activation txhawb o thiab oxidative kev nyuaj siab nyob rau hauv ib tug nas remnant raum qauv.15,95
Nrf2 activation kuj tiv thaiv lossis txo qis fibrosis. Unilateral ureteral obstruction nyob rau hauv nas ua rau down-regulation ntawm Keap1, tso cai rau kom ceev nrooj ntawm Nrf2 nyob rau hauv lub nucleus thiab induction.nrf 2-dependent gene qhia, uas tiv thaiv tiam ntawm ROS. Txawm li cas los xij, kev cuam tshuam ntev ntev ua rau muaj kev txo qis hauv nuclear Nrf2 nrog rau kev txo qis ntawm cov tshuaj tiv thaiv antioxidants thiab nce oxidative kev nyuaj siab, o, fibrosis, thiab tubular puas.96 Cov kev tshawb fawb no qhia txog qhov muaj peev xwm hloov pauv ntawmnrf 2kev qhia hauv CKD raws li kev kis kab mob txij li Nrf2 tuaj yeem raug tswj hwm nyob rau theem pib vim ROS tab sis tuaj yeem txo qis raws li tus kab mob hnyav zuj zus thiab mob hnyav dua.
Sodium-glucose cotransporter 2 inhibitors - ib chav kawm tshiab ntawm renoprotectors - tau pom los txhawb kev txo qis hauv albuminuria thiab txo kev pheej hmoo ntawm ESKD hauv ob hom 2 mob ntshav qab zib thiab tsis muaj ntshav qab zib CKD.97 Raws li ib feem ntawm cov teebmeem renoprotective ntawm sodium- qabzib cotransporter 2 inhibitors zoo li tau kho los ntawm kev txhim kho lub raum hypoxia98 nrog txo qhov mob 99 thiab txhim kho cov tshuaj tiv thaiv antioxidant, 100 nws yog qhov txaus siab uas tsis ntev los no tau tshaj tawm tias dapagliflozin inhibits apoptosis thiab activates autophagy nyob rau hauv ib feem los ntawm kev ua haujlwm ntawmnrf 2/HO-1 pathways.101
Mitochondrial Dysfunction thiab Nrf2 hauv Kev Txhim Kho ntawm CKD
Cov ntaub ntawv pov thawj qhia tau hais tias mitochondrial dysfunction txhawb txoj kev loj hlob thiab kev loj hlob ntawm CKD tsis hais txog qhov tshwm sim.13 Mitochondria yog cov organelles nyuaj nrog ntau lub zog, suav nrog kev tsim ntawm adenosine triphosphate los ntawm oxidative phosphorylation.102
Tsis ntev los no, peb txoj kev nkag siab ntawm lub luag haujlwm mitochondria ua si tau nthuav dav tshaj li adenosine triphosphate ntau lawm kom suav nrog kev txaus siab ntawm lawv txoj haujlwm ua organelles uas tswj cov txheej txheem ntawm tes, xws li kev loj hlob, kev sib txawv, thiab kev tuag.103 Mitochondria ua raws li lub hauv paus hauv lub cell, Kev paub txog kev hloov pauv hauv cellular milieu thiab sai sai redirecting metabolic intermediates kom tsim nyog raws li qhov xav tau muab tso rau ntawm lub cell.104 Nws yog tam sim no pom tseeb tias metabolic reprogramming plays lub luag haujlwm tseem ceeb hauv cov lus teb inflammatory.105 Kev ntsib tus kab mob ua rau muaj kev hloov phenotypic hauv macrophages uas yog Tus cwj pwm los ntawm kev txo qis ntawm oxidative phosphorylation thiab fatty acid oxidation thiab muaj zog nce ntawm glycolysis, lipid synthesis, thiab ROS ntau lawm.106,107 Txawm hais tias ROS yog tsim nyog rau mount ob qho tib si ib tug innate thiab ib tug adaptive tiv thaiv tiv thaiv ntau yam. invaders, xws li cov kab mob, 103 lawv overproduction ua rau oxidative Kev ntxhov siab ua rau cov ntaub so ntswg puas thiab ua haujlwm tsis zoo.30 Qhov no metabolic reprogramming yog txhais tau tias yuav ua neej nyob luv luv thiab txwv rau thaj chaw kis kab mob lossis kev puas tsuaj. Thaum cov kev ntxhov siab tau raug tshem tawm, nws yog ib qho tseem ceeb uas cov hlwb rov qab mus rau homeostasis - lub xeev sib npaug uas cov txheej txheem inflammatory raug muab tua, ROS yog nruab nrab, thiab cov metabolism hauv mitochondrial rov qab mus rau lub xeev ntawm oxidative phosphorylation.108 Hauv CKD, txawm li cas los xij, qhov no " kev hloov pauv" ua tsis tiav thiab cov txheej txheem kev puas tsuaj tau ruaj khov, thaum kawg ua rau cov ntaub so ntswg puas thiab poob ntawm lub raum ua haujlwm.44,73
nrf 2paub tias yuav txo ROS qib thiab txo qhov mob; Txawm li cas los xij, cov kev tshawb fawb tsis ntev los no tau pom tias qhov kev hloov pauv no tseem tswj hwm cov cellular thiab mitochondrial metabolism.30,109, 110, 111, 111, 112 Nrf2 directs metabolic reprogramming los ntawm kev tswj cov piam thaj thiab lipid metabolism, ua kom muaj txiaj ntsig adenosine triphosphate ntau lawm, txhawb bio mitophagsis1. Los ntawm suppressing o, txo ROS theem, thiab txhawb cov qauv thiab kev ua haujlwm zoo ntawm mitochondria, Nrf2 txhim kho lub peev xwm ntawm tes kom rov zoo los ntawm cellular stress thiab restores cellular homeostasis.109,112,113
Lub raum yog cov kab mob metabolic uas xav tau ntau ntawm adenosine triphosphate kom ua haujlwm ib txwm muaj.102 Vim lawv cov pa oxygen ntau, ob lub raum raug kev puas tsuaj los ntawm ROS, uas tuaj yeem ua kom nrawm dua.raumkab mobprogression.13,114 Overproduction of ROS and defective mitophagy, along with activation of apoptotic pathways, uas yog tswj los ntawm mitochondria, yog interconnected tsav tsheb ntawm CKD progression.13 Mitochondrial dysfunction nyob rau hauv lub raum hlwb zoo li muaj feem xyuam rau txoj kev pheej hmoo ntawmmob raum. Ntau dua mitochondrial DNA luam tus lej, tus cim surrogate ntawm kev txhim kho mitochondrial kev ua haujlwm, tau cuam tshuam nrog kev pheej hmoo qis ntawm CKD, tsis muaj kev pheej hmoo ntawm kev pheej hmoo thiab mob.115 Hauv qhov sib piv, txo qis ntawm mitochondrial-derived peptides tau cuam tshuam nrog o thiab txo. kev qhia ntawmnrf 2Nyob rau hauv CKD.116 Tsis tas li ntawd, mitochondrial dysfunction tau ntseeg tias ua lub luag haujlwm hauv lub raum fibrosis117 thiab kev loj hlob ntawm cov kab mob raum.108 Ua ke, cov kev tshawb pom no qhia tias cov khoom siv hluav taws xob metabolic no yuav yog lub hom phiaj kho mob kom txo qis kev loj hlob ntawm lub raum.mob raum.118 Ib txoj kev tshawb fawb tsis ntev los no qhia tau hais tias ib qho analog ntawm bardoxolone methyl, ib tug muaj zog activator ntawmnrf 2, confers kev tiv thaiv los ntawm proteinuria-induced mitochondrial kev puas tsuaj rau tubules ob leeg nyob rau hauv vitro thiab nyob rau hauv ib tug tsiaj qauv los ntawm kev txhim kho mitochondrial redox tshuav nyiaj li cas thiab mitochondrial muaj nuj nqi.21
Lub luag haujlwm ntawm Nrf2 rau Kev Mob Ntsws Hauv Kab Mob Raum Kab Mob
Cov kab mob sib kis thoob plaws lub spectrum ntawm lub raum kab mob
Alport Syndrome
Kev mob ntev hauv Alport syndrome, zoo ib yam li lwm yam mob uas ua rau CKD, yog qhov tshwm sim los ntawm kev ua kom tsis tu ncua ntawm kev ua kom muaj kev mob tshwm sim. nyob rau hauv Alport syndrome.2 COL4A3 knockout nas tsim proteinuria thaum ntxov li 5.5 lub lis piam ntawm hnub nyoog.119 Ntau cov protein nyob rau hauv glomerular filtrate ("pathological proteinuria") activates proinflammatory thiab profibrotic signaling pathways nyob rau hauv proximal tubular epithelial hlwb2 thiab ua rau cov kev qhia ntawm noob encoding. chemotactic molecules. Cov molecules no txhawb kev nkag mus ntawm lub cev tiv thaiv kab mob, ua rau tubular atrophy thiab tubulointerstitial fibrosis.2 TGF- kuj tseem koom nrog hauv cov txheej txheem ntawm glomerupathies thiab fibrosis.2,59,120,121 Raws li cov neeg mob Alport syndrome tau poob raum kev ua haujlwm txawm tias siv cov tshuaj angiotensin- Kev hloov pauv enzyme inhibitors thiab angiotensin-receptor blockers thiab muaj cov ntaub ntawv sau tseg inflammatory, cov teebmeem ntawmnrf 2stimulation nrog bardoxolone methyl yog tam sim no soj ntsuam nyob rau hauv ib tug randomized tswj mus sib hais (CARDINAL).122
Autosomal-Dominant Polycystic raum Kab Mob
Kev mob tshwm sim tshwm sim thaum ntxov ntawm ADPKD thaum cov neeg mob muaj lub raum ua haujlwm zoo lossis ze li qub. Cov txiaj ntsig tau los ntawm ntau qhov kev tshawb fawb txhawb nqa lub luag haujlwm rau kev mob hauv ADPKD cyst kev loj hlob thiab kev loj hlob ntawm tus kab mob. Kev tsim cov cyst tau pom ua ntej qhov sib txuam ntawm cov kab mob macrophage uas qhia tias cov hlwb no tsiv mus rau qhov chaw ntawm qhov mob o.123,124 Txoj cai ntawm cyst kev loj hlob los ntawm macrophage migration inhibitory factor muab kev txhawb nqa ntxiv rau qhov mob ua rau muaj kev txhawb nqa hauv kev loj hlob cyst thiab rau kev koom tes ntawm macrophages hauv ADPKD. .125 Cov kev tshawb fawb tsiaj kuj txhawb nqa lub luag haujlwm tseem ceeb rau kev mob hauv kev loj hlob thiab kev loj hlob ntawm ADPKD. Piv txwv li, macrophage depletion nyob rau hauv polycystin 1, ib tug transient receptor muaj peev xwm channel interacting (Pkd) 1- targeted PKD nas, ua rau ib tug tsis tshua muaj cystic phenotype thiab lub raum ua hauj lwm zoo dua.126 NF-κB tau kuaj pom nyob rau hauv lub nuclei ntawm cyst-lining cells nyob rau hauv tus nas PKD qauv, 127 thiab nce qib ntawm proinflammatory cytokines, suav nrog IL-1 , TNF, thiab IL-2, tau tshaj tawm nyob rau hauv ADPKD.128,129 Cov kev soj ntsuam no qhia tias mob o tuaj yeem Tsis tsuas yog txhawb kev pib ntawm tus kab mob thiab cystogenesis los ntawm nws cov cellular effectors tab sis kuj ua lub luag haujlwm hauv cyst expansion thiab kab mob kev loj hlob.123,125 Tseeb, nws tsis ntev los no tau tshaj tawm tias kev ua kom covnrf 2ameliorates oxidative kev nyuaj siab thiab cystogenesis hauv tus qauv nas ntawm ADPKD.91
IgA nephropathy
Inflammation nyob rau hauv IgAN tshwm sim los ntawm lub cev tsis muaj zog tsim ntawm galactose-tsis muaj IgA1 nyob rau hauv lub glomerular mesangium.130 Immune complex formation tshwm sim tom qab rau ntau sequential immunopathogenic "hits,"131, 132, 133 nrog rau induction ntawm lub zos inflammatory teb, IgliA deposition. thiab ua kom-thiab kev puas tsuaj rau-mesangial hlwb. Activated mesangial cells secrete Cheebtsam ntawm ECM thiab tso tawm ntau tus neeg nruab nrab uas ua rau lub raum raug mob, suav nrog proinflammatory thiab profibrotic cytokines, 134 uas txhawb nqa mesangial cell proliferation thiab recruitment inflammatory cells rau hauv glomerulus.132 Inflammatory mediators kuj hloov cov noob qhia hauv podocytes, ua rau podocyte raug mob ("glomerulopodocytic crosstalk") thiab pom ntawm IgA lub cev tiv thaiv kab mob, suav nrog segmental glomerulosclerosis.132,135, 136, 137, 138 Ib qho kev tshawb fawb tsiaj tau pom tias stimulation ntawm covnrf 2Txoj kev muaj peev xwm hloov kho qhov mob hauv IgAN. Nyob rau hauv nas nrog induced accelerated thiab zuj zus IgAN, stimulation ntawm lubnrf 2txoj hauv kev nrog antroquinonol inhibited T cell ua kom thiab tiv thaiv kev ua haujlwm ntawm NLR tsev neeg pyrin domain uas muaj 3 inflammasome. Nws kuj tseem txhim kho cov proteinuria, lub raum ua haujlwm, thiab histopathology hauv cov nas nrawm thiab nce qib-IgAN nrog cov kab mob tsim.139
Lub luag haujlwm ntawm Nrf2 rau Kev Mob Ntsws Hauv Kab Mob Raum Kab Mob
Mob ntshav qab zib CKD
Proinflammatory signaling pathways thiab lawv cov khoom downstream tau tshwm sim los ua cov biomarkers tshiab hauv DKD thiab tej zaum yuav tau cog lus kho cov hom phiaj hauv cov neeg mob uas muaj tus kab mob no.140 DKD cuam tshuam nrog kev ua kom cov kab mob inflammatory uas ua rau muaj kab mob sib kis141 thiab cuam tshuam nrog ntau hom kab mob ntawm tes, molecules, thiab txoj hauv kev, suav nrog macrophages, mast cells, thiab NF-κB-kev hloov pauv ntawm cov kab mob cytokines, suav nrog IL-1, IL-6, IL-18, thiab TNF.141, 142, 143 , 144, 145 Ib qho kos npe ntawm cov kab mob inflammatory uas muaj nyob rau hauv TNF receptor superfamily cov tswv cuab tau kwv yees qhov kev pheej hmoo ntawm 10- xyoo ntawm ESKD hauv ntshav qab zib, 146 qhia txog cov tshuaj tiv thaiv kab mob tuaj yeem pab ntes kev loj hlob ntawm DKD. Ultrastructural hloov nyob rau hauv glomerular qab daus daim nyias nyias yog tshwm sim los ntawm lub xub ntiag ntawm mob-theem cov cim ntawm o, xws li IL-6.147 NF-κB-induced molecules thiab txoj kev ua rau cov qauv kev hloov pauv thiab kev ua haujlwm tsis zoo ntawm DKD, thiab thaum kawg , raum tsis ua hauj lwm nyob rau hauv cov neeg mob.141 Lub luag hauj lwm raunrf 2nyob rau hauv DKD tau pom nyob rau hauv ib txoj kev tshawb fawb ntawm cov nas mob ntshav qab zib qhia tau hais tias lub raum tsis ua hauj lwm muaj kev cuam tshuam nrog oxidative kev nyuaj siab thiab txo translocation ntawmnrf 2mus rau hauv lub nucleus.148 tau los ntawm kev tshawb fawb ntawm streptozotocin-kho, Nrf2-knockout nas qhia txo kev tiv thaiv o, impaired raum ua haujlwm, fibrosis, thiab oxidative puas.149
Focal Segmental Glomerulosclerosis
Txawm hais tias podocyte raug mob thiab poob yuav yog thawj tsav tsheb ntawm FSGS, 150 qhov mob kuj tseem xav tias yuav ua lub luag haujlwm tseem ceeb hauv kev kis tus kab mob.151,152 Kev koom tes ntawm o hauv etiology ntawm FSGS tau tawm tswv yim los ntawm kev tshawb pom qhov sib txawv ntawm qhov sib txawv ntau dua {{ 3}}T cells zoo thiab macrophages hauv lub raum biopsies los ntawm cov neeg mob nrog FSGS.153 Oxidative stress kuj ua rau lub pathogenesis ntawm FSGS.154 Kev puas tsuaj rau podocytes ua rau muaj kev raug mob ntxiv los ntawm cytokine tso tawm (xws li, TGF- ), uas ua rau cov Recruitment ntawm monocytes, macrophages, thiab T hlwb thiab txhim kho kev qhia thiab tso tawm ntawm lwm yam cytokines (piv txwv li, IL-1 thiab TNF) thiab chemokines.152 Baseline raum ua haujlwm hauv cov neeg mob FSGS yog inversely correlated nrog lub ntiaj teb sclerosis thiab tubulointerstitial fibrosis, suav nrog urinary excretion ntawm IL-12, interferon- , IL-4, IL-5, thiab IL-13.155 Kev nkag mus ntawm cov kab mob inflammatory hauv FSGS ua rau tsuj ntawm mesangial ECM, uas tuaj yeem ua rau glomerular collapse ("collapsing variant").152 Kev puas tsuaj rau tubular epithelial hlwb ua rau kev hloov mus rau mesenchymal hlwb, uas ua rau collagen matrix deposition thiab tubulointerstitial fibrosis.152,156 Qhov no proinflammatory thiab profibrotic milieu tau koom nrog hauv kev loj hlob. ntawm FSGS thiab tej zaum yuav ua rau glomerular caws pliav thiab qhov tshwm sim ESKD.157 Lub luag haujlwm raunrf 2nyob rau hauv kev loj hlob ntawm FSGS tau pom nyob rau hauv Imai nas qauv, nyob rau hauv uas impaired Nrf2 signaling nyob rau hauv ua ke nrog NF-κB activation txhawb o thiab oxidative kev nyuaj siab, ob qho tag nrho cov uas muaj feem xyuam rau kev loj hlob glomerulosclerosis.158
Xaus
Mounting pov thawj qhia txog lub luag haujlwm tseem ceeb ntawm kev mob thiab cov kab mob metabolic nyob rau hauv kev loj hlob ntawm CKD ntawm ntau yam kev sib txawv. .23 Steady-state mRNA qhia cov qauv thoob plaws lub spectrum ntawm CKD yog ua raws li cov kev cai ntawm inflammatory genes.23nrf 2Txoj hauv kev ua haujlwm ua lub hub txuas cov kab mob metabolic thiab inflammatory pathways nyob rau hauv CKD.23 Repressed qhia ntawm no cytoprotective yam yog txuas rau ntau yam pathogenic mechanisms paub los txhawb fibrosis thiab kev loj hlob ntawm.kab mob raum, xws li senescence, o, mitochondrial dysfunction, thiab cov ntaub so ntswg hypoxia; yog li ntawd,nrf 2Kev ua kom muaj zog yog lub hom phiaj txaus nyiam rau kev ntes cov kev loj hlob ntawm CKD.12,13,61,62 Augmenting qhov kev txiav txim ntawm Nrf2 thiab nws cov neeg nruab nrab hauv qab hauv CKD muaj peev xwm ua rau kom txo qis, ntes, lossis thim rov qab qhov poob ntawm lub raum ua haujlwm.
Lub luag haujlwm ntawm Nrf2 rau Kev Mob Ntsws Hauv Kab Mob Raum Kab Mob
Qhia tawm
PS: Pawg kws qhia txuj ci rau Reata Pharmaceuticals, Inc., AstraZeneca, Vifor Pharma, thiab Baxter Healthcare. GMC: Pawg Thawj Coj ntawm Satellite Healthcare, Inc.; Tus kws pab tswv yim / tus kws pab tswv yim rau Akebia Therapeutics, Amgen, Ardelyx, Inc., AstraZeneca, Baxter Healthcare, CloudCath, Cricket Health, DiaMedica Therapeutics, Inc., Direct Corp, DxNow, Inc., Gilead Sciences, Inc., Miromatrix Medical, Inc., Outset Medical, Reata Pharmaceuticals, Inc., Sanifit, thiab Vertex Pharmaceuticals Inc. PD: pawg thawj coj saib xyuas kev kho mob rau Reata Pharmaceuticals, Inc.; hais lus bureau rau BioPorto Inc.; tus thawj coj tswv yim tseem ceeb rau Alnylam Pharmaceuticals thiab Dicerna Pharmaceuticals; coinventor ntawm xa patents rau kev siv NGAL ua biomarker ntawm lub raum raug mob; Daim ntawv tso cai pom zoo nrog Abbott Diagnostics thiab BioPorto Inc. rau kev txhim kho NGAL ua biomarker ntawm lub raum raug mob. AL: Pawg Kws Pab Tswv Yim rau Reata Pharmaceuticals, Inc.; Cov nyiaj pab los ntawm Otsuka America Pharmaceutical, Inc., AstraZeneca, thiab Boehringer Ingelheim International GmbH. SPA: tus kws pab tswv yim rau Alexion Pharmaceuticals thiab Reata Pharmaceuticals, Inc. SB: pawg neeg pab tswv yim rau Reata Pharmaceuticals, Inc. BAW: pawg neeg pab tswv yim rau Reata Pharmaceuticals, Inc.; pawg kws kho mob ntawm Alport Syndrome Foundation; tus kws pab tswv yim rau Bayer AG, Akebia Therapeutics, Relypsa, Inc., Amgen, FibroGen, Inc., thiab UpToDate, Inc.; Kev tshawb fawb txhawb nqa los ntawm National Institutes of Health thiab Baxter Healthcare.
Kev lees paub
Txoj haujlwm no tau txais kev txhawb nqa los ntawm Reata Pharmaceuticals, Inc.
Sau Kev Pab Txhawb
PS, GMC, thiab BAW tau sau cov ntawv sau. PD, AL, SPA, thiab SP muab kev nkag siab txog kev kho.
Khoom siv ntxiv
Cov ntaub ntawv ntxiv (PDF).
Daim duab S1. Molecular mechanism ntawm Keap 1-nrf 2Lub kaw lus thaum lub sij hawm oxidative kev nyuaj siab teb76 Raws li ib txwm muaj, Nrf2 yog degraded thiab inactivated tom qab raug ntes los ntawm Keap1 homodimers. Nyob rau hauv cov xwm txheej ntawm oxidative kev nyuaj siab, kev sib cuam tshuam ntawm Keap1 thiab Nrf2 yog inactivated, ua rau txo qis.nrf 2degradation. Nuclear translocation ntawm stabilized Nrf2 tso cai rau transcriptional activation ntawm Nrf2 lub hom phiaj noob. Cys, cysteine residues; Keap1, kelch-zoo li ECH-txuas nrog cov protein-1; Nrf2, nuclear factor, erythroid 2 zoo li 2; Ub, ubiquitin-proteasome-dependent degradation. Luam tawm nrog kev tso cai los ntawm Nezu M li al. Targeting KEAP{10}}NRF2 system los tiv thaivmob raumkev vam meej. Yog J Nephrol. 2017; 45(6):{3}}. Copyright © 2017 Karger Publishers, Basel, Switzerland.
Daim duab S2. Kev loj hlob ntawmmob raumRaws li ib feem ntawm cov txheej txheem kev laus ntxov ntxov hauv CKD.87 Cov tshuaj lom uremic milieu txhawb kev mob thiab kev tawm tsam ntawmnrf 2, ib qho tshwm sim txuas rau oxidative kev nyuaj siab, mitochondrial tsis ua hauj lwm, cov ntaub so ntswg hypoxia, thiab senescence. Cov ntaub ntawv pov thawj qhia tias cov yam ntxwv no yog cov tsav tsheb loj ntawm lub hnub nyoog ntxov ntxov hauv CKD, suav nrog kev laus thaum ntxov (vascular calcification), sarcopenia, osteoporosis, plawv tsis ua hauj lwm, kev nyuaj siab, thiab kev paub tsis meej. Tsis tas li ntawd, cov yam ntxwv zoo ib yam tuaj yeem ua rau muaj kev laus thaum ntxov hauv lub raum los ntawm lub raum fibrosis thiab o. Ntxiv nrog rau hemodynamic thiab metabolic yam, o thiab fibrosis tuaj yeem ua rau muaj kab mob raum, tsim kom muaj lub voj voog vicious. Cov kws kho mob nephrologists tuaj yeem cuam tshuam rau qhov xwm txheej no los ntawm kev siv cov tswv yim tsim kho tshiab, thiab cov tswv yim kho mob yav tom ntej, xws li ACEi/ARB, SGLT2i, Nrf2 agonist, thiab MR inhibitors. Angiotensin-hloov enzyme inhibitor / angiotensin-receptor blocker (ACEi / ARB); CKD, mobmob raum; MR, mineralocorticoid receptor;nrf 2, nuclear factor, erythroid 2 zoo li 2; sodium-glucose thauj protein 2 inhibitor (SGLT2i).
Cov ntaub ntawv
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