Ntu 1 Heme Oxygenase 1: Tus Kws Kho Mob Tiv Thaiv Kab Mob raum

Ntu 1

Anne Grunenwald¹, Lubka T. Roumenina¹thiab Marie Frimat ^2,3,*

Abstract:Qhov xwm txheej ntawmraumCov kab mob tau nce ntxiv, ua rau lub nra tseem ceeb ntawm kev saib xyuas kev noj qab haus huv thiab ua rau kev txheeb xyuas cov hom phiaj kho mob sai sai. Lub heme oxygenase (HO) system ua lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm oxidative kev nyuaj siab thiab o thiab, ntawm cov txheej txheem no, xav tias ua lub luag haujlwm hauv kev tiv thaiv kev raug mob uas tsis yog tshwj xeeb tom qab mob raum tsis ua haujlwm lossis ua rau mob raum mob. Qhov kev qhia ntawm HO-1 yog qhov tsis txaus ntseeg los ntawm ntau yam kev txhawb nqa hauvraum, ua rau lub raum pom lub luag haujlwm uas txhais tau hais tias HO-1 raug rau ntau yam ntawm endogenous thiab exogenous molecules, thiab nws tau pom tias muaj kev tiv thaiv nyob rau hauv ntau hom tsiaj neuropathological. Qhov zoo siab, qhov txiaj ntsig zoo ntawm HO-1 tshwm sim hauv ob qho tib si hemolysis- thiab rhabdomyolysis-dominated kab mob, qhov twgraumfeem ntau raug rau heme (ib qho loj HO-1 inducer), nrog rau cov kab mob uas tsis yog-heme-dependent xws li kub siab, ntshav qab zib nephropathy, lossis kev loj hlob mus rau theem kawg ntawm lub raum kab mob. Qhov no qhia txog qhov nyuaj ntawm HO-1 cov haujlwm, uas kuj tau piav qhia los ntawm qhov tseeb tias, txawm tias muaj ntau cov ntaub ntawv kho mob, tsis muaj tshuaj tsom rau HO-1 kom deb li deb tau muab txhais ua kev kho mob. Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog txhawm rau txheeb xyuas cov kev paub tam sim no ntsig txog HO-1 lub luag haujlwm hauv lub raum thiab nws cov txiaj ntsig zoo li nephroprotection tus neeg sawv cev. Lub peev xwm kho tau qhib yuav raug nthuav tawm, tshwj xeeb los ntawm kev txheeb xyuas cov kev sim tshuaj ntsuam xyuas cov enzyme no lossis nws cov khoom.

Ntsiab lus:heme-oxygenase-1; haum;raum; hemolysis; rhabdomyolysis; toxicity; ischemia-reperfusion

Hu rau: ali.ma@wecistanche.com

Cistanche extract pab rau cov kab mob raum, nyem qhov no kom tau txais cov qauv

1. Taw qhia

Tus naj npawb ntawm cov neeg thoob ntiaj teb uas muaj mob ntevraumkab mob (CKD), mob raum raug mob (AKI), lossis xav tau kev kho lub raum hloov ntau dua 850 lab [1]. Qhov kev kwv yees tau tshwm sim yog qhov ua rau muaj kev txhawj xeeb, nrog CKD tau npaj los ua lub ntiaj teb thib tsib ua rau tuag los ntawm 2040 [2]. Nws yog feem ntau lees txais tiasraumCov kab mob yog ib qho teeb meem tseem ceeb rau pej xeem kev noj qab haus huv thiab hais tias qhov kev xav tau ntawm ntau txoj hauv kev los tiv thaiv qhov kev hloov pauv uas xav tau yog qhov xav tau sai sai [3]. Qhov tseem ceeb ntawm qhov tseem ceeb yog kev txheeb xyuas cov hom phiaj kho tshiab, ob qho tib si txhawm rau txwv qhov cuam tshuam ntawm lub raum mob hnyav thiab txhawm rau txo cov txiaj ntsig tsis zoo hauv CKD, thoob plaws ntau yam ntawm cov hauv qab etiologies. Ntau tus neeg sib tw rau nephroprotection tam sim no tau kawm [4,5]. Lub heme oxygenase (HO) system yog ib lub hom phiaj uas tuaj yeem siv los tiv thaiv lub raum los ntawm kev puas tsuaj los ntawm oxidative kev nyuaj siab, txwv tsis pub muaj kab mob thiab ua rau muaj kev laus sai.

HO tau tshawb pom nyob rau xyoo 1968 los ntawm Tenhunen thiab cov npoj yaig, uas thawj zaug piav qhia nws lub peev xwm los ua kom muaj kev tawg ntawm heme (Fe-protoporphyrin IX) kom dawb hlau, carbon monoxide (CO), thiab biliverdin, uas tau hloov pauv sai rau bilirubin [6]. Ob lub ntsiab isoforms ntawm HO tau piav qhia: inducible HO-1 thiab constitutive HO-2. Thaum xub thawj tsuas yog suav tias yog ib qho kev rov ua dua tshiab rau heme los ntawm cov qe ntshav liab hnub nyoog, HO tau raug ntaus nqi ntau ntawm cytoprotective zog los ntawm nws cov metabolites thiab downstream signaling, nthuav nws cov ntsiab lus los ntawm lub "molecular wrecking pob" mus rau ib tug "mesmerizing" trigger ntawm Cov xwm txheej ntawm tes, los hais txog Maine thiab al. [7]

Tsav los ntawm nws cov muaj peev xwm antioxidant thiab tiv thaiv kab mob, HO-1 yog cov ntsiab lus ntawm kev txaus siab rau nws lub luag haujlwm hauv tib neeg pathologies. Ntawm cov kev tshawb fawb hauv nruab nrog cev, lub raum feem ntau tau hais txog ntau dua 30 xyoo dhau los, tshwj xeeb los ntawm kev txheeb xyuas lub luag haujlwm rau HO-1 hauv ntau lub raum, cov kab mob metabolic thiab vascular ntawm ob qho tib si mob thiab mob ntev [8-11. ]. HO-1 yog qhov tseem ceeb rau kev ua tau zooraumkev ua haujlwm, raws li tau piav qhia los ntawm lub raum kev puas tsuaj rau tib neeg nrog HO-1 tsis txaus thiab los ntawm kev tshawb fawb tsiaj ntau (piv txwv li hauv qab). Covlub cevphysiological ua haujlwm tshwj xeeb cuam tshuam rau HO-1 kev cai. Tseeb tiag, lub raum cov ntaub so ntswg yog heev raug rau hypoxia [12], ib tug loj tsav tsheb ntawm HO-1 qhia, thiab tshwj xeeb tshaj yog raug rau cov tshuaj lom molecules vim nws filtration thiab reabsorption functions. Qhov tshwj xeeb ntawm kev ua "detoxification" lub cev, sib koom nrog lub siab, txhais tau hais tias lub raum raug cuam tshuam rau kev puas tsuaj rau cov qauv molecular (DAMPs) thiab cov neeg muaj kev ntxhov siab. Interestingly, lubraummuaj lub peev xwm rau cov synthesis ntawm albumin, alpha protein, thiab haptoglobin nyob rau hauv ischemic los yog lom ischemic puas, underlining lub parallel nrog lub siab [13,14]. Lub raum hlwb, yog li ntawd, xav tau cov tswv yim hloov kho los khaws lawv cov haujlwm thiab kev ncaj ncees nyob rau hauv ib puag ncig hnyav. Lub raum yog qhov chaw loj ntawm kev raug mob heme nyob rau hauv cov xwm txheej ntawm extravascular hemolysis los yog rhabdomyolysis, thiab li no kuj rau induction ntawm HO-1 qhia. Raws li cov xwm txheej no, HO-1 overexpression tau yooj yim piav qhia los ntawm qhov xav tau catabolize qhov dawb heme overload. Txawm li cas los xij, HO-1 kev koom tes hauv cov kab mob hauv lub raum mus dhau lub ntsiab lus ntawm cov kab mob heme, qhia txog qhov nyuaj ntawm nws cov txheej txheem ntawm kev ua haujlwm uas txuas mus dhau heme catabolism ib leeg [15].

Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog los piav qhia txog qhov loj ntawm cov kev sim thiab cov ntaub ntawv kho mob piav qhia txog qhov tseem ceeb ntawm HO-1 hauvraum, yam tsis tau hnov ​​qab tias HO-2 kuj tseem ceeb: kev tsim tawm hauv lub raum nyob rau hauv cov xwm txheej hauv tsev, nws yog thawj kab ntawm kev tiv thaiv ischemia thiab lwm yam kev thuam, thiab nws lub raum cytoprotective teebmeem tau tshwm sim hauv heme protein- thiab ischemia-induced AKI [16]. Piv nrog rau cov ntaub ntawv hais txog HO-1, txawm li cas los xij, muaj tsawg heev cov kev tshawb fawb soj ntsuam cov kev ua haujlwm tseem ceeb ntawm HO-2 hauv cov kab mob raum; yog li ntawd, qhov kev tshuaj xyuas no yuav tsom mus rau HO-1. Tom qab kev qhia dav dav rau cov yam ntxwv ntawm HO-1 hauv lub raum, peb yuav piav qhia txog lub luag haujlwm ntawm cov enzyme no hauv cov neeg mob raum thiab cov kab mob hauv lub raum. Muab nws lub luag haujlwm tseem ceeb ntawm kev rov ua dua heme, peb yuav mus rau cov xeev pathological raws li seb puas muaj kev tso tawm loj ntawm heme dawb. Thaum kawg, cov ntawv thov kev kho mob tam sim no yuav raug nthuav tawm, qhia qhov tsis sib xws ntawm qhov kev nthuav dav ntawm cov ntaub ntawv sim muaj thiab cov txheeb ze ntawm kev siv tshuaj kho mob.

2. Hais txog Heme Oxygenase-1 hauv raum

2.1. Vim li cas HO-1 Tshwj xeeb tseem ceeb rau lub raum?

Ob peb lub xyoo dhau los, lub luag haujlwm tseem ceeb ntawm HO-1 system hauv pathophysiology ntawmraumkab mob tau txais kev txhawb los ntawm ntau qhov kev tshawb fawb. Hauv ob HO-1-cov neeg mob tsis txaus qhia txog niaj hnub no, lub raum yog nyob rau hauv cov kabmob uas puas lawm. Ob tus neeg mob muaj hematuria thiab proteinuria.Lub raumbiopsies qhia tau hais tias nce mesangial proliferation thiab focal thickening ntawm capillary loops los ntawm lub teeb microscopy, thiab endothelial detachment nyob rau hauv lub glomerular capillary los ntawm electron microscopy [17,18]. Kev raug mob rau lub raum kuj tseem muaj nyob rau hauv ob qho tib si tsiaj qauv invalidated rau HMOX1, nrog qee qhov sib txawv ntawm cov nas [19] thiab nas qauv [20]. Nyob rau hauv Hmox1-/- nas, tsis muaj kev ua haujlwm heme oxygenase yog lub luag haujlwm rau kev txhim kho qhov cuam tshuam rau oxidative kev nyuaj siab [19], txo qis hemophagocytosis ntawm cov qe ntshav liab los ntawm cov nqaij mos macrophages, nce hemolysis, thiab redistribution ntawm hlau los ntawm splenic thiab hepatic. macrophages rau hepatocytes thiab lub raum proximal tubule hlwb [21] Ib yam li ntawd, Hmox1-/- nas pom muaj ntshav liab, splenomegaly, thiab tseem ceeb interstitial inflammatory cell infilltrates thiab fibrosis caws pliav hauv lawv ob lub raum. Thaum cov kab mob glomerular yog ib qho kev tsis txaus ntseeg hauv tus qauv nas, Atsaves li al. pom qhov nce hauv mesangial matrix thiab focal thiab segmental glomerulosclerosis lesions hauv Hmox1-/- nas. Cov kev tshawb pom morphological no tau cuam tshuam nrog cov ntshav urea nitrogen, ntshav creatinine, thiab albuminuria, tab sis qhov nthuav dav tsis muaj qhov nce ntawm cov hlau tso rau hauv glomeruli, tubules, lossis interstitium [20].

Lub raum puas tsuaj nyob rau hauv tib neeg thiab tsiaj qauv invalidated rau HMOX qhia tias HO-1 yog ib qho tseem ceeb rau lub raum ua hauj lwm zoo. Lub luag haujlwm tiv thaiv lub raum ntawm cov enzyme no tau raug lees paub hauv ntau cov qauv ntawm lub raum kev sib tw hauv HO-1 invalidation/inhibition lossis overexpression condition [22]. Txawm li cas los xij, qhov sib txawv histological tau hais los saum toj no qhia txog qhov nyuaj ntawm kev hloov pauv los ntawm ib hom mus rau lwm tus. Qhov sib txawv ntawm kev tswj hwm ntawm HO-1 ntawm tib neeg thiab nas tau piav qhia tau zoo, txhawb kev tsim ntawm tib neeg hHO-1 BAC transgenic nas [23]. Nyob rau hauv cov qauv no, HO-1 yog overexpressed, thiab nws tseem tsis tau paub hais tias seb qhov kev nthuav qhia ntau dua tom qab no yuav tsis pom kev puas tsuaj rau lub sijhawm ntev, lossis txawm tias muaj kev cuam tshuam tsis zoo rau nws tus kheej.

Kev nkag siab zoo dua ntawm HO-1 ua haujlwm li cas hauvraum, thiab nws cov lus qhia lossis kev ua haujlwm raug tswj li cas, yog qhov tseem ceeb rau peb nkag siab txograumphysiology thiab pathology tab sis nws yog (raws li ib txwm muaj) tseem ceeb kom nco ntsoov cov kev txwv ntawm ib qho kev kawm hauv nws txoj kev txhais lus thiab kev txhais lus: peb yuav sim txhawb nqa qhov kev xav tseem ceeb thoob plaws hauv qhov kev tshuaj xyuas no.

2.2. Kev cai ntawm HO-1 Kev nthuav qhia hauv raum

HO-1 protein yog ubiquitous, raug khi rau hauv daim nyias nyias ntawm endoplasmic reticulum thiab tseem nyob hauv mitochondrial nuclei thiab caveolin, thaum lub HO-1 noob (HMOX1), uas encodes HO-1, yog nyob rau ntawm Chromosome 22. Ntau yam stimuli tuaj yeem hloov kho qhov kev hloov pauv ntawm HMOX1, cuam tshuam qhov dav ntawm DNA-binding motifs nyob rau hauv nws cov neeg txhawb nqa thiab ntau txoj hauv kev taw qhia uas ua rau nws cov ntawv sau. Lub ntsiab tswj hwm ntawm HMOX1 noob yog nuclear erythroid yam 2 (Nrf2), uas nws ua kom nyob ntawm nws cov kev cuam tshuam nrog Kelch-hom, ECH-txuas nrog cov protein (Keap1). Kev sib cuam tshuam Keap-Nrf2 txhawb kev degradation ntawm Nrf2 (lub xeev noj qab haus huv), thaum tsis muaj kev ruaj ntseg ntawm no complex tso Nrf2 uas translocates mus rau hauv lub nucleus thiab upregulates tej genes, xws li HO-1 (stressed xeev). Muaj ntau ntau lwm yam activators los yog repressors ntawm HO-1 tsim ib tug complex biomolecular network (ntau yam nyob rau hauv yav dhau los xyuas [7,10]). Cov ntsiab lus ntawm cov no dhau ntawm qhov kev tshuaj xyuas no thiab peb yuav nyob ntawm no tsom mus rau lub raum tshwj xeeb ntawm HO-1 qhia.

Hauvraum, HO-1 cov qib protein tsis tuaj yeem kuaj pom nyob rau hauv cov xwm txheej hauv tsev, tshwj tsis yog hauv cov tubules uas nws tseem nyob qis [24]. Ntau yam kev ntxhov siab tau paub txog kev tswj hwm lub raum transcription HO-1, suav nrog oxidative stress, heat shock, hypoxia, hnyav hlau, thiab co toxins (saib hauv Bolisetty li al. [8]). Raws li cov xwm txheej no, HO-1 kev qhia tseem nyob ntawm qhov sib txawv ntawm lub raum. Lub raum muaj ob qhov chaw tseem ceeb: cov zis cortex thiab medulla nyob rau hauv cheeb tsam innermost. Lub medulla muaj feem ntau ntawm qhov ntev ntawm cov nephrons, cov khoom ua haujlwm ntawm lub raum uas lim dej los ntawm cov ntshav. Lub raum cortex suav nrog cov glomeruli, cov "tufts" ntawm capillaries qhov twg cov ntshav tau lim los ntawm glomerular hauv qab daim nyias nyias. Cov kua lim dej ces ntws los ntawm lub convoluted proximal tubule mus rau lub voj ntawm Henle, thiab tom qab ntawd mus rau lub convoluted distal tubule thiab sau ducts, uas ntws mus rau hauv lub ureter (Daim duab 1). Glomerular filtration thiab reabsorption ntawm solutes (lub raum ob lub luag haujlwm tseem ceeb) tau txais kev txhawb nqa los ntawm lub raum cov ntshav ntws, uas yog qhov siab tshaj plaws hauv lub cev, nrog rau lub raum tau txais txog 20 mus rau 25 feem pua ​​​​ntawm cov zis. Piv nrog rau lub cortex, cov ntshav ntws mus rau lub raum medulla yog qhov tsawg. Qhov kev sib txawv no yuav tsum tau ua kom muaj txiaj ntsig zoo ntawm cov zis tso zis thiab tseem piav qhia txog qhov tshwj xeeb ntawm cov medulla kom txo cov ntshav ntws. Raws li kev ntxhov siab, HO-1 yog li nthuav tawm ntau dua hauv medulla dua li cortex [25]. Nws cov lus qhia muaj zog heev nyob rau hauv tubules (tshwj xeeb tshaj yog cov tubules ze), tab sis tsawg heev los yog tsis muaj nyob rau hauv glomeruli, raws li qhia nyob rau hauv daim duab 2 nyob rau hauv ob qho tib si hemolytic cov neeg mob thiab heme-injected nas. Txawm li cas los xij, nws tau pom tias ua ntej induction ntawm HO-1 nyob rau hauv lub glomeruli tiv thaiv kev loj hlob ntawm nephrotoxic glomerulonephritis nyob rau hauv ib tug Lewis nas qauv, tab sis tus tsim loj ntawm HO-1 nyob rau hauv lub glomeruli yog cov infilltrating macrophages, tsis yog lub cev glomerular hlwb [26] Lub peev xwm qis dua ntawm glomeruli no los qhia HO-1, uas yog ib qho tseem ceeb cytoprotective mechanism, tuaj yeem piav qhia txog glomeruli qhov tshwj xeeb rhiab heev rau cov kev ntxhov siab hauv qee yam pathologies [27].

Muab ua ke, cov ntaub ntawv no qhia tau tias HO-1 qib ib txwm tsis tuaj yeem kuaj pom hauvraumtab sis qhov ntawd HO-1 yog qhov tsis txaus ntseeg hauv cov tubules thaum lub sij hawm pathologies, tshwj xeeb tshaj yog los ntawm nws qhov tseem ceeb tshaj tawm Nrf2. Lub peev xwm ntawm glomeruli los ntxias HO-1 qis dua, txawm li cas los xij.

2.3. HO-1 thiab Nephroprotection

Zoo li HO-2, HO-1 tsav NADPH-nyob ntxiv ntawm cov pa oxygen molecule rau lub nplhaib porphyrin ntawm heme, yog li catalyzing oxidation ntawm heme thiab equimolar tso tawm ntawm biliverdin, dawb hlau, thiab carbon oxide. (CO). Tag nrho cov xwm txheej no yog cytoprotective los ntawm kev tshem tawm cov heme dawb, tswj cov hlau efflux, thiab nce qib bilirubin thiab CO. Tseeb tiag, cov teebmeem tsis zoo ntawm cov heme dawb tau piav qhia tau zoo, tshwj xeeb tshaj yog nyob rau ntawm qhov chaw vascular los ntawm kev toxicity ncaj qha, tab sis kuj los ntawm kev stimulation ntawm pro-inflammatory signaling pathways (xws li DAMPs) thiab ua kom lub zog ntxiv [28]. Zoo ib yam li cov hlwb endothelial, cov teebmeem tsis zoo no tau tshaj tawm nrog lwm hom cell thaum raug mob heme. Qhov no yog cov ntaub ntawv rau tib neeg lub cev nqaij daim tawv nqaij fibers, uas raug rau heme induces contractile dysfunction [29], thiab raum tubular hlwb [30]. Tsis tas li ntawd, hlau yog tshwj xeeb tshaj yog lom txawm nyob rau hauv tsawg concentrations. Nws koom nrog Fenton cov tshuaj tiv thaiv, tsim cov hydroxyl, thiab tuaj yeem ua rau lub cell tuag los ntawm ferroptosis, txoj kev tuag ntawm tes los ntawm kev txo qis ntawm cov hlau-dependent ntawm glutathione (GSH) qib thiab tsub zuj zuj ntawm lipid hydroperoxides mus rau theem tuag [31]. Yog li, nws tau raug tshaj tawm tias cytoprotection ntawm HO-1 yog vim li cas, tsawg kawg ntawm ib feem, rau ib qho ntxiv ntawm cov hlau flux [32], uas tom qab nws tso tawm yog khaws cia hauv ferritin lossis xa tawm los ntawm macrophages rau ntshav rau re. -siv ntawm transmembrane ferrous exporter ferroportin. CO tiv thaiv vasoconstriction thiab muaj zog tiv thaiv oxidant, zoo li biliverdin, uas yog enzymatically hloov mus rau bilirubin ntawm biliverdin reductase [33].

Transposing cov khoom no mus rau lub raum theem, nws yog ib qho yooj yim to taub kev tshawb fawb txaus siab rau harnessing no molecule thiaj li yuav kho.raumkab mob. Cov txiaj ntsig zoo tau piav qhia txog yuav luag 30 xyoo, tom qab kev ua haujlwm ntawm Nath li al., uas tau tshaj tawm tias HO-1 tau muab kev tiv thaiv hauv nas qauv ntawm glycerol-induced, mob raum tsis ua haujlwm. Hauv lawv cov qauv, ib qho kev txhaj tshuaj ua ntej ntawm hemoglobin sai ua rau HO-1 tus xa xov RNA thiab cov protein nyob hauv lub raum, uas tiv thaiv kev mob raum tsis ua haujlwm [34]. Cov teebmeem nephroprotective ntawm HO-1 thiab nws cov metabolites txij li thaum tau tshaj tawm nyob rau hauv ntau hom kab mob raum [8,35]. Lub peev xwm tseem ceeb ntawm HO-1 nyob rau hauv lub pathogenesis ntawm lub raum kab mob kuj pom zoo los ntawm kev sib txuas ntawm polymorphisms hauv HO-1 noob thiab lub raum tshwm sim. Cov tib neeg uas luv dua (GT)n rov ua dua hauv HO-1 cheeb tsam txhawb nqa muaj kev ua haujlwm siab dua thiab yog li HO{11}} qib siab dua li cov tib neeg uas ntev dua (GT)n rov ua dua [36]. Interestingly, ntev (GT)n rov ua dua tau cuam tshuam nrog qhov tshwm sim tsis zoo hauv ntau lub ntsiab lus, uas yog, muaj kev pheej hmoo siab dua rau AKI tom qab phais plawv lossis txo qis rau lub raum ua haujlwm tom qab hloov lub raum [37,38]. Txawm li cas los xij, tsis muaj pov thawj ntawm kev tiv thaiv ntawm luv luv rov ua dua (GT)n rau graft lossis tus neeg tau txais kev muaj sia nyob tom qab hloov lub raum [39], qhia txog qhov nyuaj ntawm cov txheej txheem cuam tshuam. Cov theem ntawm HO-1 kev qhia kuj yuav txawv raws li hnub nyoog. Lub raum qhia ntawm cov noob HO-1 hauv kev tswj C57Bl6 nas tau txo qis thaum muaj hnub nyoog 18 piv nrog 3 lub hlis ntawm hnub nyoog [40]. Hauv lwm txoj kev tshawb fawb, cov protein HO-1 qhia tsis txawv qhov txawv ntawm qhov pib ntawm 6–{25}}cov nas hnub nyoog ib lim piam thiab 1-cov nas muaj hnub nyoog, tab sis cov tsiaj laus muaj peev xwm txhawb nqa HO -1 nyob rau hauv cov lus teb rau ischemia-reperfusion raug mob (IRI) tau ua tsis taus (tshwj xeeb tshaj yog nyob rau hauv lub medulla), thiab lawv pom lub raum tsis ua hauj lwm zoo dua piv nrog cov tsiaj hluas [41]. Cov txiaj ntsig no ua rau lub raum rhiab heev ntawm cov neeg laus rau cov tshuaj nephrotoxic.

Los xaus, kev tiv thaiv lossis caj ces induction ntawm HO-1 kev qhia tau pom nyob rau hauv ntau cov kev tshawb fawb los muab kev tiv thaiv raum. Kev txo qis hauv lub raum HO-1 kev qhia tuaj yeem ua raulub cevrhiab heev rau qee yam pathologies.

3. HO-1 nyob rau hauv lub raum Cell Populations

Kev txheeb xyuas sib piv tau qhia tias HO-1 tsis tau qhia rau tib yam hauv cov neeg ntawm tes sib txawv ntawmraumrau ib qho kev txhawb nqa (Daim duab 1). Thaum lub sij hawm intravascular hemolysis los yog nyob rau hauv lub xub ntiag ntawm HO-1-inducing kev nyuaj siab stimuli los yog tshuaj nyob rau hauv txoj kev, lub endothelial hlwb yog cov thawj hlwb uas yuav tsum tau sib tw los ntawm cov systemic stressors. Yog hais tias tus stressor lim nyob rau hauv lub glomeruli, ces cov podocytes raug thiab tej zaum yuav puas, raws li pom nyob rau hauv mob ntshav qab zib nephropathy. Ntxiv mus, tus stressor yuav ntsib mesangial hlwb uas muaj secretory thiab immunomodulatory luag hauj lwm thiab proliferate thaum lub sij hawm HO-1 deficiency. Thaum kawg, qhov kev ntxhov siab tuaj yeem ncav cuag tubular epithelium uas yog hom cell feem ntau kawm txog kev sib raug zoo rau HO-1 (cov tubules ze ze thiab cov distal yuav tsum tau txiav txim siab sib cais nrog rau cov epithelium). Tubular epithelial hlwb muaj lub peev xwm tshaj plaws rau kev tshaj tawm HO-1 thiab raug kev raug mob hnyav tshaj plaws nyob rau hauv rooj plaub ntawm nws qhov tsis txaus lossis thaum lub sij hawm intravascular hemolysis thiab rhabdomyolysis. Nqe lus no piav qhia txog lub luag haujlwm tseem ceeb ntawm lub raum cell hom thiab lub luag haujlwm tshwj xeeb ntawm HO-1 hauv lawv.

3.1. Endothelial Cells

Lub endothelium yog tsim los ntawm monolayer ntawm endothelial hlwb (EC) uas ua tiav cov haujlwm tseem ceeb hauv cov hlab ntsha. Lawv npog cov hlab ntsha sab hauv thiab ua haujlwm tsis zoo, tab sis lawv kuj ua haujlwm sib pauv nrog cov ntaub so ntswg uas nyob ib sab, ib qho sensor rau cov ntaub so ntswg thiab intravascular kev nyuaj siab, thiab raws li lub hauv paus ntawm kev tiv thaiv kev sib kho [42]. Yog li ntawd, EC yog thawj kab ntawm cov hlwb kom ntsib kev ntxhov siab thiab HO-1 kev qhia yog qhov tseem ceeb rau lawv txoj sia nyob, nrog HO-1-cov neeg mob tsis zoo thiab cov qauv murine uas nthuav tawm qhov kev puas tsuaj ntawm endothelial [19,43]. Cov txiaj ntsig ntawm kev muaj sia nyob ntawm HO-1 hauv EC tshwm sim hauv txhua lub cev thiab muaj lub cev loj ntawm kev ua haujlwm txog nws qhov induction los ntawm ntau yam molecules [44,45]. Raws li nws qhov chaw hauv cheeb tsam (hauv cov kabmob sib txawv, hauv cov hlab ntsha lossis cov hlab ntsha), EC qauv, tshwj xeeb thiab kev ua haujlwm sib txawv. Yog li, EC los ntawm cov txaj vascular sib txawv muaj cov lus qhia zoo (spatially thiab temporally) thiab qhov no yuav piav qhia lawv cov kev xaiv kev koom tes hauv cov txheej txheem kab mob sib txawv [42].

Hauvraum, peb hom tseem ceeb ntawm endothelium tuaj yeem paub qhov txawv: glomerular, peritubular capillary, thiab nruab nrab / loj hlab ntsha endothelium [46], txhua qhov sib txawv ntawm HO-1 kev qhia lossis kev ua haujlwm. Glomerular EC yog "fenestrated" thiab them los ntawm glycocalyx [47] lub luag haujlwm rau txwv tsis pub nkag mus rau macromolecule mus rau hauv lub urinary chamber [48]. Txawm hais tias glycocalyx, me me hydrophobic molecules (xws li, heme) tuaj yeem nkag mus rau hauv cov ntaub so ntswg ntawm tes thiab qhib txoj hauv kev proinflammatory thiab prothrombotic, suav nrog TLR-4 signaling, yog li txhawb cov ntshav cell adhesion thiab vaso-occlusion (Schaer et al., 2013). Peritubular capillaries 'EC kuj yog fenestrated thiab nteg raws li nyias stroma. Lawv thauj cov khoom reabsorbed, txhawb nqa tubular epithelial cell muaj nuj nqi [46]. Thaum kawg, lub endothelia ntawm ob qho tib si nruab nrab thiab loj cov hlab ntsha yog contiguous, nrog interconnected EC. Cov txheej txheem thiab kev ua haujlwm sib txawv ntawm EC hauv lub raum raws li kev ua haujlwm ntawm lawv qhov chaw ua rau lawv sib txawv rau cov kev ntxhov siab tshwj xeeb, xws li tshuaj lom lossis cov kua dej ua kua dej rau glomerular EC, hypoxia rau peritubular capillaries, lossis kev hloov pauv hauv kev ntxhov siab, nrog rau cov lus teb tshwj xeeb. Yuav ua li cas ua kom lub ntsej muag [46]

Lub ntsiab yam tseem ceeb cuam tshuam rau HO-1 qhia hauv EC yog hypoxia, shear stress, muaj heme, thiab lwm yam circulating stressors (ammonia [49], S-adenosyl methionine [50], thiab lwm yam), circulating tshuaj (statins. [51], resveratrol [52], thiab lwm yam) lossis tshuaj. Cov pa ib nrab siab txo qis raws peritubular capillary, tshwj xeeb tshaj yog nyob rau hauv kev ntxhov siab nrog ntau O2 noj. Interestingly, HO-1 qhia tau hais tias yuav txo tau raws li hypoxia thaum HO-2 qhia tau khaws cia nyob rau hauv macrovascular human umbilical vein EC (HUVEC) [53]. Txawm li cas los xij, HO-1 kev qhia yog inducible nyob rau hauv microvascular peritubular capillaries 'EC nyob rau hauv ntau yam mob uas yuav provoke hypoxia (heme, Angiotensin II, thiab lwm yam). Physiological shear stress yog ib qho tseem ceeb ntawm EC ciaj sia taus, raws li qhia nyob rau hauv vivo nyob rau hauv tib neeg carotid atherosclerotic plaques [54] thiab luav carotids nrog txo cov ntshav ntws [55]: nws kuj induces cov kev qhia ntawm anti-inflammatory yam tseem ceeb (hauv vitro hauv HUVEC thiab hauv vivo hauv luav aorta [56]) thiab vasodilatory sawv daws yuav (hauv vitro thiab vivo hauv nas [57]). Interestingly, HO-1 kev qhia yog tshwm sim los ntawm shear stress, nyob rau hauv vitro nyob rau hauv macrovascular (aorta) thiab microvascular (HMEC) tib neeg EC [58], thiab cov lus qhia no tau qhia nyob rau hauv nas kom ncaj qha rau theem ntawm shear stress. : kev nthuav qhia ntau dua ntawm cov dej ntws siab (hauv cov hlab ntsha), tab sis yuav tsum tau ua lwm yam rau HO-1 kom qhia tau qis qis (hauv microvessels) [59]. Qhov tshwm sim tam sim no tsuas yog tau tshaj tawm hauv cov hlab ntsha hauv plab. Txawm li cas los xij, yog tias cov txiaj ntsig no tau txheeb xyuas hauv lwm lub cev, nws tuaj yeem piav qhia txo qis HO-1 induction hauv capillaries xws li glomerular EC nyob rau hauv kev ntxhov siab [27]. EC tau raug pom zoo rau cov khoom lag luam cytotoxic hemolysis-derived thiab cov lus teb endothelial rau cov kev thuam no cuam tshuam txog kev sib txawv ntawm EC. Microvascular EC, thiab tshwj xeeb tshaj yog glomerular EC, tsis tshua muaj kev tswj hwm HO-1 piv nrog macrovascular EC, ob qho tib si hauv vitro thiab hauv tus nas qauv ntawm hemolysis [27]. Qhov no ua rau lawv tshwj xeeb rau kev raug mob los ntawm qhov sib txawv ntawm lawv cov kev cai C3 ntxiv thiab heme degradation piv nrog macrovascular EC [27]. Me ntsis paub txog HO-1 induction muaj peev xwm ntawm peritubular capillaries 'EC.

Lub raum macrovascular EC tseem kawm tsis zoo nrog rau HO-1 kev qhia thiab kev ua haujlwm. Cov qauv siv dav tshaj plaws hauv kev tshawb fawb ntawm macrovascular EC yog tib neeg txoj hlab ntaws EC (HUVEC). Kev cuam tshuam rau heme hauv HUVEC yog lub luag haujlwm rau kev xa cov teeb liab sai, kev txav ntawm lub cev endothelial Weibel Palade, thiab NF-kB ua kom muaj zog, yog li muab lawv ib qho pro-inflammatory thiab pro-thrombotic phenotype [60–62]. Txawm li cas los xij, ntev ntev tso cai rau lawv los tsim kho cov txheej txheem hloov kho thiab ua rau cov oxidative-stress-mediated raug mob thiab lipid peroxidation cov khoom. Cov no suav nrog induction ntawm ferritin thiab HO-1 [63], txawm tias HO-1 induction hauv glomerular EC hauv vitro thiab hauv cov qauv nas ntawm hemolysis yog qhov tsis muaj zog [27,64]. HO-1 induction nyob rau hauv macrovascular EC qhov tseem ceeb ntawm kev ua kom muaj zog ntxiv [27,65], thrombomodulin qhia hauv hemolysis mob [27] thiab hauv cov ntsiab lus ntawm septicraumraug mob [66], thiab kev qhia ntawm adhesion molecules txuam nrog EC ua kom [67].

Ua ke, cov ntaub ntawv no qhia tias covraumendothelium muaj zog cuam tshuam los ntawm co toxins thiab stressors raws li nws cov filtration muaj nuj nqi. Cov kev ntxhov siab no zoo li ua rau muaj zog hloov kho cov txheej txheem hauv macrovascular EC uas tso cai rau lawv tawm tsam kev thuam rau qee theem, feem ntau yog los ntawm kev tswj hwm ntawm HO-1 thiab nws cov noob caj noob ces. Txawm hais tias muaj cov ntaub ntawv tsis txaus ntseeg hauv cov ntaub ntawv, cov kev tshawb fawb muaj qhia tias, piv rau macrovascular EC, qhov HO-1 upregulation no tsis tshua muaj nyob rau hauv glomerular microvascular endothelium, ua rau nws tshwj xeeb tshaj yog rau ib puag ncig kev ntxhov siab.

3.2. Podocytes

Podocytes yog cov hlwb tshwj xeeb uas tswj cov glomerular filtration barrier los ntawm kev sib txuas ntawm glomerular hauv qab daus daim nyias nyias (GBM) thiab tsim cov slit diaphragm los ntawm kev txuas lawv cov txheej txheem ko taw mus rau glomerular endothelial hlwb [68] (Daim duab 1). Lawv cov tswv yim hauv zos, ua kom lawv cov kev ua haujlwm pom, ua rau lawv tshwj xeeb rau kev siv tshuab, oxidative, thiab kev tiv thaiv kab mob. Podocytes muaj cov lus teb tshwj xeeb, suav nrog kev tswj hwm ntawm vimentin thiab desmin [69], lossis cov proteins antioxidant xws li Sirtuin1 thiab metallothionein. Sirtuin upregulates Nrf2, yog li txhim kho HO-1 qhia. [70,71] Txaus siab rau, sirtuin-1 kev qhia (ua ke nrog Nrf2 thiab HO-1) tau tshaj tawm tias tau nce ntxiv los ntawm kev cuam tshuam rau qib siab glycation kawg-cov khoom lag luam [71], thiab HO{{14} } tau pom tias muaj kev txhim kho tshwj xeeb hauv podocytes hauv cov neeg mob ntshav qab zib [72]. Txawm hais tias tsawg dua kev kawm, qhov kev qhia ntawm HO-1 kuj tau piav qhia nyob rau hauv cov xwm txheej hemolytic [27,73], nrog heme inducing HO{19}} qhia nyob rau hauv ib qho Nrf2-dependent yam hauv podocytes. Interestingly, Nrf2-cov nas tsis muaj zog tau tsim cov proteinuria nrog cov txheej txheem ko taw effacement txo qis synaptopodin thiab nephrin qhia, thiab podocyte apoptosis [73].

Txawm hais tias cov ntaub ntawv ntawm HO-1 hauv podocytes tsis muaj ntau, cov pov thawj dab tsi muaj qhia tias muaj lub luag haujlwm tiv thaiv lub cev rau Nrf2 / HO-1 axis los ntawm kev khaws cov pedicels thiab inhibiting kev tuag thiab detachment ntawm podocytes. Nyob rau hauv cov ntsiab lus pathological, HO-1 yog overexpressed raws li ib tug tiv thaiv mechanism tab sis kuj yuav yog ib tug byproduct ntawm lub zog tiv thaiv mechanisms los ntawm kev nyuaj siab, nyob rau hauv uas cov ntsiab lus nws yog tsis txaus los tiv thaiv podocyte raug mob.

3.3. Mesangial Cells

Mesangial hlwb, ua ke nrog cov mesangial matrix lawv tsim, tsim cov mesangium, cov ntaub so ntswg txhawb rau glomerulus floculus. Ntawm cov hlwb mesangial yog cov hlwb tiv thaiv kab mob, monocyte / macrophage-zoo li (5 mus rau 15 feem pua), thiab cov qog nqaij hlav, uas zoo ib yam li cov leeg nqaij (85 mus rau 95 feem pua) thiab muab kev txhawb nqa thiab kev cog lus [74,75]. Heme txhawb kev loj hlob ntawm cov leeg nqaij pob txha [76] thiab nws cov receptor TLR4 tau nthuav tawm ntawm cov hlwb mesangial [77], tab sis lub luag haujlwm ntawm HO-1 hauv cov hlwb no tau kawm tsis zoo. Nitric oxide (NO) tau pom tias ua rau HO-1 hauv cov hlwb mesangial [78], HO-1-cov neeg mob tsis txaus muaj mesangial proliferation [17,18,43], thiab HO{{17} } tau pom los hloov kho mesangial cell proliferation ntawm p21 upregulation [79]. Kev ua haujlwm ntxiv yog xav tau los txiav txim siab seb lub cev loj ntawm kev paub sau rau macrophages puas siv tau rau cov macrophage zoo li mesangial hlwb.

3.4. Tubular Cells

Yog hais tias HO-1 qhia tau piav nyob rau hauv tubules ib lub sij hawm dhau los, nws tsuas yog tsis ntev los no hais tias nws txoj cai tau piav raws li yog ib feem tshwj xeeb; HO-1 kuj tseem ua lub luag haujlwm sib txawv hauv ntu sib txawv ntawm cov tubule txhawm rau tswj lub raum ua haujlwm [80].

3.4.1. Proximal Tubule

Lub proximal tubules yog cov cell hauv lubraumuas qhia lub peev xwm siab tshaj plaws rau kev tshaj tawm ntawm HO-1. Tseeb tiag, proximal tubular epithelial hlwb tau pom tias tshwj xeeb tshaj yog rau oxidative kev nyuaj siab hauv vitro [81]. Lawv vam khom rau HO-1 rau kev tiv thaiv los ntawm, thiab hloov mus rau, kev ntxhov siab, raws li pov thawj los ntawm qhov tseeb tias tubular raug mob yog qhov tseem ceeb ntawm cov kab mob hauv tib neeg HO-1 deficiency [82]. Lub luag haujlwm tseem ceeb ntawm lub raum proximal tubule yog kev nqus dej, ions, amino acids, thiab lim cov proteins. Thaum tsis muaj glomerular puas, lim cov proteins feem ntau ntawm qhov loj dua 68kDa. Internalization ntawm cov proteins, suav nrog cov heme-koom nrog xws li myoglobin lossis hemoglobin, tab sis kuj hemopexin, tshwm sim ntawm megalin thiab tubulin receptors [83]. Qhov no reabsorption muaj nuj nqi yuav tsum muaj ntau lub zog (ATP) muab los ntawm mitochondrial beta-oxidation [84]. Txawm li cas los xij, ATP depletion hnyav ua rau muaj kev raug mob mitochondrial, ua rau muaj kev puas tsuaj ntxiv ntawm cov khw muag khoom hluav taws xob thiab tsim cov hom pa oxygen reactive [85]. Qhov kev xav tau siab metabolic no ua rau lub xeev ntawm cov txheeb ze hypoxia hauv lub raum medulla, thiab cov tubules ze ze yog qhov tshwj xeeb tshaj yog rau ischemia / reperfusion thiab heme ntau dhau [86,87]. Qhov rhiab heev rau heme kuj tau piav qhia los ntawm kev qhia ntawm TLR4 (ib qho heme receptor) los ntawm cov tubules ze ze [61], thiab TLR4 qhia tau nce ntxiv hauv lub raum ischemia-reperfusion raug mob thiab septic raug mob [77].

Thaum HO-1 tsuas yog qhia tsis muaj zog hauv qhovraumNyob rau hauv ib txwm muaj mob, nws muaj zog inducible nyob rau hauv proximal tubules nyob rau hauv ntau hom kev ntxhov siab [88], proteinuria ntawm lawv [80]. Kev sib koom ua ke ntawm kev txhawb nqa ntawm heme-muaj proteins, osmotic siab tsav heme influx, TLR4 qhia, thiab nce synthesis ntawm heme nyob rau hauv cov tubules proximal yuav ua ke piav qhia qhov tshwj xeeb, muaj zog upregulation ntawm HO-1. Nws tau raug pom zoo tias HO-1 kev qhia hauv tubular epithelial hlwb nyob ntawm ntau dua li ntawm basolateral raug rau heme (los ntawm peritubular capillaries nyob rau hauv hemolytic tej yam kev mob) tshaj intraluminal heme cov ntsiab lus. Txawm li cas los xij, nyob rau hauv cov xwm txheej ntawm hypoxia thiab ntawm qhov hloov pauv ntawm lub raum EC, HO-1 upregulation tau raug tshaj tawm tias muaj kev vam khom ntau dua li qhov raug rau heme [89]. Hauv tubular epithelial hlwb, HO-1 upregulation los ntawm heme yog nyob ntawm Nrf2 stabilization [90]. HO-1 muaj ob lub luag haujlwm hauv tubular EC, ua ib txhij los tiv thaiv oxidative thiab tswj kev tuag ntawm tes. Tseeb tiag, HO-1 yog lub luag haujlwm rau kev tswj hwm ntawm p21, cyclin-dependent kinase inhibitor lub luag haujlwm rau kev txwv tsis pub lub voj voog ntawm tes, uas txo qis apoptosis hauv tubular EC [91,92]. Tsis tas li ntawd, HO-1 qhia txo qis ferroptosis nyob rau hauv cov tubular proximal hlwb, uas tsis yog-apoptotic tswj cell tuag txuam nrog tsub zuj zuj ntawm reactive oxygen hom (ROS) muab los ntawm lipid peroxidation [93]. Thaum kawg, HO-1 tau pom tias inhibit autophagy hauv cov cell tubular [94].

Ua ke, cov cell tubular ze ze tau nthuav dav rau HO-1 inducers nyob rau hauv cov ntsiab lus pathological (filtration of hemoglobin, myoglobin, hemopexin-heme complexes; ischemia, filtration of toxic products or drug, etc.) thiab cia siab rau HO{{2. }} rau lawv txoj kev tiv thaiv, tab sis HO-1 kuj yog ib qho cim ntawm tubular kev nyuaj siab thiab raug mob thaum lawv lub peev xwm rau kev hloov pauv tau dhau mus.

3.4.2. Distal Tubule

Distal tubular EC raws lub medulla, tshwj xeeb tshaj yog nyob rau hauv tuab, nce limb ntawm lub voj ntawm Henle (mTAL) thiab lub distal convoluted tubule (DCT), muaj kev koom tes nyob rau hauv cov concentration thiab dilution ntawm cov zis thiab kev saib xyuas ntawm homeostatic ntsev thiab cov kua qaub theem los ntawm nthuav tawm cov channel sib txawv tshwj xeeb rau lawv qhov chaw nyob thiab subtype ntawm tes. Thaum lub sij hawm reabsorption dej, qhov concentration ntawm co toxins (tseem ceeb heme) ua ntau dua nyob rau hauv lub distal nephron ntu. Vim tias qhov tsis tshua muaj siab ntawm cov pa oxygen raws cov peritubular capillaries, cov tubular EC no tshwj xeeb tshaj yog muaj kev cuam tshuam rau hypoxia thiab vam khom ntau dua ntawm anaerobic, glycolytic ATP ntau dua li cov cell ze ze. Distal tubules muaj peev xwm muaj sia nyob ntau dua thiab hloov mus rau kev ntxhov siab hypoxic [95], tsis tshua nkag siab rau kev tuag ntawm tes, tshwj xeeb tshaj yog tom qab ischemic raug mob [96].

Distal tubules, zoo li cov tubules ze ze, tsuas yog tsis muaj zog qhia HO-1 ntawm qib basal; Raws li kev txhawb nqa, txawm li cas los xij, nws qhov kev cuam tshuam los ntawm heme tau raug hu mus rau lo lus nug [88]. (Qhov zoo siab, HO-2 tej zaum yuav txhim kho los ntawm heme hauv distal tubules [97].) Txawm li cas los xij, HO- 1 lub luag haujlwm hauv cov tubules distal tseem yuav tsum tau ua kom tiav raws li nws cov lus qhia kuj tau txuam nrog kev txhim kho. Lub raum ua haujlwm tom qab ischemia / reperfusion hauv cadaveric pub hloov pauv [98], nrog rau hauv CKD [99]. Qhov no tej zaum yuav muaj feem xyuam rau cov kev tsim kho tshiab ntawm distal tubular epithelial hlwb, tab sis xav tau kev tshawb fawb ntxiv los piav qhia txog kev sib raug zoo ntawm HO-1 thiab distal tubular epithelial hlwb cov haujlwm.

Los xaus, thaum cov ntaub ntawv hais txog cov tubules distal tsis muaj, qee cov pov thawj qhia tias kev txhim kho HO-1 kev qhia tuaj yeem muab kev tiv thaiv rau cov tubules 'EC.