Ntu 2 Heme Oxygenase 1: Tus Kws Kho Mob Tiv Thaiv Kab Mob raum
Mar 21, 2022
Ntu 2
Anne Grunenwald1, Lubka T. Roumenina1thiab Marie Frimat2,3,*
Nyem qhov no mus rau Part 1
Hu rau: ali.ma@wecistanche.com
Nyem rau cistanche cov txiaj ntsig thiab kev mob tshwm sim rau tus kab mob raum
4. HO-1 hauv Kab Mob Raum
HO-1 thiab nws induction nyob rau hauv ntau yamraumpathologies thiab physiological tej yam kev mob aroused txaus siab nees nkaum xyoo dhau los, tshwj xeeb tshaj yog nyob rau hauv cov ntsiab lus ntawm loj heev dawb heme tso, xws li uas txuam nrog hemolytic kab mob thiab rhabdomyolysis [100]. Txawm li cas los xij, HO-1 tau nthuav tawm lub luag haujlwm tiv thaiv hauv ntau lwm yam pathologies uas tsis yog classical suav tias yog heme-mediated nephropathies. Qhov no suav nrog ischemia / reperfusion raum raug mob thiab tubular nephropathies (uas tej zaum yuav muaj tshuaj lom), septic thiab obstructive nephropathies, thiab, ntxiv rau, glomerular nephropathies. Qhov kev faib tawm ntawm tus kab mob no sawv cev rau ntau qhov sib txawv ntawm HO-1 stimulating stressors (Daim duab 3). Tseeb tiag, ischemia ua raws li kev rov ua dua tuaj yeem yog ib feem ntawm cov txheej txheem ntawm lub raum raug mob hauv hemolytic pathologies [101] thiab rhabdomyolysis [102]. Ntawm qhov tod tes, lub zos heme tso tawm tsis ntev los no tau tshaj tawm nyob rau hauv kev sim ischemia-reperfusion [103], thiab tej zaum ib qho tseem ceeb hauv ischemia / reperfusion-txog pathologies xws li raum hloov pauv, txawm tias tsis yog qhov tseem ceeb ua rau muaj kev puas tsuaj [104]. Tsis tas li ntawd, cov ntshav plasma siab ntawm cov heme dawb tau raug ntsuas hauv qee qhov pathologies tsis tau suav tias yog qhov cuam tshuam nrog heme, xws li sepsis [105]. Tom qab hais tias qhov no, peb yuav txiav txim siab txog ob feem ntawm cov spectrum los piav qhia txog kev tiv thaiv lub luag haujlwm ntawm HO-1 nyob rau hauv ob qho tib si nyob rau hauv lub xub ntiag thiab tsis muaj intrarenal heme overload.
4.1. Cov Kab Mob Sib Kis nrog Kev Tso Tawm Loj Loj ntawm Heme Dawb
Ob pawg dav ntawm pathology cuam tshuam nrog kev tso tawm loj ntawm heme, uas yog, kab mob hemolytic thiab rhabdomyolysis. Hauv cov kab mob hemolytic, heme raug tso tawm los ntawm hemoglobin tom qab tawg ntawm cov qe ntshav liab. oxidation ntawm Hb thiab liberation ntawm heme tuaj yeem tshwm sim hauv kev ncig lossis hauv cov tubules, tom qab pom Hb dimers hauv glomeruli. Thaum lub sij hawm rhabdomyolysis, myoglobin los ntawm cov leeg pob txha raug mob nkag mus
kev ncig, tab sis heme tsis tso tawm rau ntawd vim nws qhov kev sib raug zoo siab dua rau cov protein no piv rau Hb. Hloov chaw, myoglobin yog lim los ntawm glomeruli, thiab heme raug tso tawm hauv interstitium, tshwj xeeb tshaj yog tom qab noj cov protein no los ntawm cov tubules ze. Hauv ob qho xwm txheej, HO-1 tau tswj hwm ntau heev hauvraum. Siv ob peb yam piv txwv, peb yuav piav qhia thiab txheeb xyuas lub luag haujlwm ntawm HO-1 hauv cov kab mob cuam tshuam nrog kev tso tawm loj ntawm heme.
4.1.1. Cov Kab Mob Hemolytic
Hemolysis yog ib hom kab mob pathological uas suav nrog ntau yam etiologies uas tuaj yeem tshwm sim hauv intra- lossis extravascularly. Intravascular hemolysis yog kev puas tsuaj ntawm cov qe ntshav liab (RBCs) nyob rau hauv txoj kev, uas tej zaum yuav muaj teeb meem ntawm extravascular hemolysis, los yog lwm yam tshwm sim mechanically xws li nyob rau hauv thrombotic microangiopathy, malignant hypertension, los yog los ntawm mechanical heart valve implants [28]. Extravascular hemolysis yog tshem tawm ntawm RBCs nyob rau hauv tus po, siab, lossis pob txha pob txha los ntawm phagocytes. Nws yog feem ntau txuas rau qhov tsis xws luag uas tuaj yeem ua rau sab hauv (nrog rau cov kab mob caj ces xws li mob qog noj ntshav ntshav lossis kis kab mob xws li paroxysmal nocturnal hemoglobinuria (PNH)) lossis extrinsic (xws li autoimmune hemolytic anemia, mob siab cirrhosis). Hauv ob qho xwm txheej, lysed RBCs tso tawm hemoglobin, nws pib-oxidization uas tso tawm dawb heme uas muaj pro-oxidative thiab pro-inflammatory zog. Haptoglobin thiab hemopexin nyob rau hauv cov hlab ntsha scavenge hemoglobin thiab heme, feem, thiab tsav lawv tshem tawm. Txawm li cas los xij, cov txheej txheem tiv thaiv no tau ploj mus sai thiab tsis tuaj yeem tiv thaiv hemoglobin thiab heme los ntawm kev ua phem thaum muaj teeb meem hemolytic loj. Qhov tseeb, cov qib heme dawb tau pom tias tau nce siab hauv cov neeg mob ntshav siab (SCD) cov neeg mob (4–50 umol) [106–108] thiab tus qauv nas ntawm SCD (75–120 uM) [109]. Qhov cuam tshuam rau kev mob tshwm sim ntawm qhov seem dawb heme thiab dawb hemoglobin tuaj yeem ua rau lub cev puas tsuaj, suav nrograum[110]. Tshwj xeeb, hemoglobin cam khwb cia nephropathy tau raug tshaj tawm hauvraumbiopsies ntawm cov neeg mob uas muaj hemolysis nrog ntau yam etiologies, xws li PNH, autoimmune hemolytic anemia, hemoglobinopathies, thiab kev mob ntshav siab [111]. Hais txog cov heme dawb uas khiav tawm ntawm hemopexin scavenging, tsuas yog HO tuaj yeem ua rau nws tsis zoo thiab cov kauj ruam detoxifying no yog qhov tseem ceeb thaum lub sij hawm hemolysis, raws li qhia thaum lub sij hawm hemoglobin infusion hauv HO-1-cov nas tsis muaj zog uas ua rau mob raum tsis ua haujlwm thiab cim kev tuag [112]. Txawm li cas los xij, ua ntej piav qhia txog kev koom tes ntawm HO-1 hauv cov kab mob hemolytic tshwj xeeb, peb yuav ua ntej tshuaj xyuas cov txiaj ntsig tseem ceeb los ntawm tus qauv siv tau siv tau thiab dav siv nas qauv ntawm intravascular hemolysis, uas yog, phenylhydrazine (PHZ) kho. Tom qab ntawd, peb yuav tsom mus rau lub ntsiab hemolysis etiologies txuam nrograumKev raug mob thiab kev hloov pauv hauv HO-1 qhia, uas yog: mob qog nqaij hlav ntshav ntshav, hemolytic uremic syndrome, malaria, thiab PNH.
PHZ-Induced Hemolysis Model
Qhov feem ntau-siv hauv vivo qauv rau intravascular hemolysis ntiav ib qho kev txhaj tshuaj hemolytic PHZ. Nws induces loj RBC kev puas tsuaj los ntawm daim nyias nyias lipid peroxidation [113] thiab destabilization ntawm hemoglobin. Pom zoo raws li kev kho mob nyob rau hauv nruab nrab -20th caug xyoo rau cov neeg mob polycythemia (tsis muaj kev vam meej), nws tau siv ntau tshaj 200 daim ntawv los kawm txog hemolysis hauv cov tsiaj sim. PHZ-kho nas muaj qhov nthuav qhia tubular ntawm HO-1 [114,115], uas tuaj yeem tiv thaiv tau los ntawm kev tswj hwm ntawm Zinc Protoporphyrin (ZnPP) [116]. Qhov kev hloov kho no yog xav tias yog Nrf2 nyob ntawm seb Nrf2-cov nas tsis muaj qhov tshwm sim muaj qhov hnyav dua, hemolysis-induced AKI phenotype, txhim kho tubular raug mob cim (KIM-1 thiab NGAL), thiab kev tuag ntawm tes, nrog rau qis HO-1 thiab ferritin [117]. Txawm li cas los xij, lwm cov kev tshawb fawb qhia tias txawm hais tias HO-1 qhia tau siab, lub raum hloov pauv hauv cov qauv no tsawg kawg yog ib feem ntawm heme, vim tias kev txhaj tshuaj dawb heme tsis tuaj yeem tsim tawm, thiab kev tswj hwm ntawm heme scavenger hemopexin tsis tuaj yeem tiv thaiv lawv. hauv PHZ qauv [115]. Yog hais tias ntxiv overactivation nyob rau hauv PHZ-induced hemolysis muaj feem xyuam rau cov ntaub so ntswg puas [118], HO{19}} kev qhia zoo li tsis muaj kev ywj pheej ntawm nws, txawm tiasraumKev raug mob phenotype, txij li kev qhia ntawm HO-1 yog piv rau cov tsiaj qus (WT) thiab C3-/-, PHZ-kho [118] thiab factor H (FH)-pretreated nas [119]. Yog li ntawd, HO-1 kev qhia zoo nkaus li nyob ntawm cov xwm txheej hemolytic es tsis yog kev sib koom ua ke ntawm tubular raug mob [119], thiab hemopexin tiv thaiv kev ua kom tiav hauv PHZ qauv yam tsis cuam tshuam rau HO-1 qhia [120]. Yog li HO-1 hauv PHZ qauv tiv thaiv lub raum los ntawm heme-dependent raum hloov pauv, tej zaum tsis muaj kev cuam tshuam ntxiv rau kev ua kom muaj zog lossis lwm yam kev raug mob heme- ywj pheej.
Sickle Cell Anemia
Sickle cell anemia (SCA) yog ib hom kab mob monogenic, uas muaj cov kab mob Hb hloov pauv (HbS), uas tuaj yeem ua polymerize thiab yog li deform erythrocytes, txo lawv txoj sia [101]. Hauv zos hypoxia nyob rau hauv ib cheeb tsam txwv, piv txwv li, thaum lub sij hawm vaso-occlusive ntsoog, tsub kom lawv lub peev xwm polymerization thiab instability thiab induces loj, intravascular hemolysis uas yuav hloov lub raum qauv thiab ua hauj lwm [121,122]. Ob leeg SCA thiab nws lub xeev heterozygous (sickle cell zoo, nrog rau qhov attenuated phenotype), yog txuam nrog kev pheej hmoo ntawm CKD [123]. Ntxiv nrog rau cov kab mob cell susceptibility rau hemolysis, HbS tsis ruaj khov thiab nquag ua rau nws pib oxidation thiab tso tawm ntawm nws cov cofactor heme.Lub raumKev raug mob hauv SCA tau piav qhia los ntawm qhov tshwm sim ntawm cov kab mob endothelial vasculopathy ua rau lub raum tsis ua haujlwm hemodynamics thiab nrog rau hyperglomerular filtration thiab hyperfunction ntawm cov tubules proximal. Cov yam ntxwv no muaj feem xyuam nrog kev raug mob glomerular xws li Focal Segmental Glomerulosclerosis (FSGS) thiab interstitial chronic inflammation (secondary to medullary hypoperfusion), ob qho tib si yog lub luag haujlwm rau CKD [121]. HO-1 kev qhia tau nce hauv lub raum tubules, cov hlwb interstitial, thiab hauv vasculature ntawm biopsies los ntawm cov neeg mob SCA piv nrog rau lub raum ib txwm [124]. Txawm li cas los xij, HO-1 tsis tau tswj hwm hauv cov hlwb mesangial, txawm tias nquag mesangial cell proliferation hauv SCA [125], qhia tias nws tuaj yeem kho ncaj qha los ntawm heme raws li tau tham saum toj no [76]. Interestingly, ntev GT tandem repeats, lub luag hauj lwm rau txo inducibility ntawm HO-1 qhia [126], nws tus kheej txuam nrog qhov tshwm sim ntawm AKI nyob rau hauv ib tug monocentric SCA cov neeg mob cohort [127], tsa qhov muaj peev xwm ntawm kev tiv thaiv ntawm HO. -1 qhia hauv cov neeg mob; HO-1 kev qhia kuj raug ntxias hauv lub raum ntawm ntau yam SCA nas qauv [124,128,129]. Qhov kev qhia murine no zoo li yog cov khoom nruab nrog cev: piv nrog cov nas tswj (Townes-AA), lub raum thiab lub siab HO-1 qhia tau 10-fold ntau dua hauv Townes SS nas (tus qauv SCD validated), tab sis tsuas yog 3- rau 4-fold ntau dua hauv lub plawv thiab tus po [128]. Tsis tas li ntawd, nyob rau hauv kev soj ntsuam thoob ntiaj teb ntawm SCA cov neeg mob, HO-1 thiab nws cov khoom los ntawm cov khoom lag luam tau raug tswj hwm hauv cov hlab ntshav mononuclear hlwb ua ke nrog cov noob koom nrog hauv heme metabolism, kev tswj lub voj voog ntawm tes, cov tshuaj tiv thaiv antioxidant thiab kev ntxhov siab, kev mob thiab angiogenesis [130], uas qhia tau hais tias circulating mononuclear hlwb tuaj yeem koom nrog hauv kev them nyiaj rau mob hlwb vascular raug mob. SCD cov neeg mob tau nthuav tawm cov pej xeem nce ntxiv ntawm cov kab mob monocytes uas qhia txog qib siab ntawm HO-1 nrog cov khoom tiv thaiv kab mob (37 feem pua vs. lub luag haujlwm ntawm cov hlwb ncig qhia HO-1 [131]. Interestingly, CO (ib qho ntawm cov khoom lag luam ntawm heme degradation los ntawm HO-1) tau pom zoo tias muaj kev koom tes hauv hyperperfusion thiab hyperfiltration (ob leeg pom hauvraumntawm SCA cov neeg mob [121,132,133]), thiab yog li tuaj yeem cuam tshuam cov vasoconstrictive cuam tshuam ntawm NO depletion los ntawm hemoglobin scavenging [108], nrog rau vasa recta rarefaction hauv medulla [134].
Microparticles (MPs-enriched nyob rau hauv heme nyob rau hauv SCA) kuj koom nyob rau hauv lub raum pathology los ntawm inducing endothelial raug mob thiab pab kom mob, vaso-occlusive xwm txheej nyob rau hauv transgenic SAD nas [129]; lawv kuj tau raug qhia los txhawb HO-1 qhia hauv tib neeg EC [135]. Thaum kawg, cov kev tshawb fawb tsis ntev los no tau txheeb xyuas lub luag haujlwm tseem ceeb rau kev ua kom muaj zog ntau dhau ntawm cov ntaub so ntswg puas tsuaj pom hauv SCD [115,136,137], tab sis raws li tau tham txog kev cuam tshuam rau PHZ qauv, HO-1 kev qhia zoo li tsis muaj kev ywj pheej ntawm kev ua kom tiav. Lwm tus qauv ntawm nas SCD tau tshaj tawm pom tias txo qis vascular congestion thiab down-regulation ntawm raug mob-txog noob caj noob ces nyob rau hauv kev sib piv nrog cov nas tsis kho (tus qauv SCD muaj -globin hloov los ntawm transgenes rau tib neeg S thiab S-Antilles globins ntawm C57Bl6 keeb kwm yav dhau, thiab tau kho. ntev nrog SnPP, lub sij hawm luv luv HO-1 inhibitor uas tseem ua rau HO{16}} qhia lub sijhawm ntev [138]). Qhov no cuam tshuam qhov tsis muaj qhov tshwj xeeb ntawm SnPP, uas twb tau hais kom siv rau lwm tus protoporphyrin [139,140]. Hauv kev xaus, muaj pov thawj rau ob qho tib si hauv zos thiab cov kab ke (los ntawm cov kab mob sib kis) kev tiv thaiv ntawm HO-1 ntawm ob qho tib siraumhemodynamics thiab theem ntawm pro-oxidant kev nyuaj siab nyob rau hauv SCA-koom nrog raum raug mob.
Yog li, HO-1 tau cuam tshuam hauv SCA nrog rau kev khaws cia ntawm lub raum hemodynamics hauv zos thiab kev tiv thaiv ntawm endothelial thiab tubular hlwb tiv thaiv oxidative kev nyuaj siab.
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome (HUS) yog qhov tsis tshua muaj,raum-predominant, thrombotic microangiopathy (TMA) muaj feem xyuam rau kev tsis sib haum xeeb ntawm txoj kev sib txuas ntxiv (AP-"atypical" lossis aHUS) thiab / lossis muaj cov tshuaj lom Shiga zoo li, zais los ntawm cov kab mob (" raug" lossis STEC-HUS Ib.) [141]. Kev tsim ntawm fibrin-platelet clots nyob rau hauv glomerular microvessels, txhawb los ntawm endothelial pro-inflammatory activation, ua rau intrarenal mechanical hemolysis. Cov noob caj noob ces los yog tau txais kev ua kom tsis muaj zog hauv aHUS, lossis kev qhia ntawm Shiga-zoo li cov tshuaj lom los ntawm cov kab mob hauv STEC-HUS, txawm li cas los xij, tsis tau piav qhia tag nrho qhov tshwm sim ntawm cov kab mob no vim nws qhov kev nkag mus tsis tiav hauv ob qho tib si thiab kev txaus siab hauv heme yog qhov tseem ceeb ntxiv. hauv kev puas tsuaj endothelial tau nce [60]. Tubular HO-1 staining los ntawm immunohistochemistry tau tshaj tawm hauvraumbiopsies los ntawm ob tus neeg mob aHUS, ntawm qhov sib npaug rau qib ntawm hemolysis; tsis muaj glomerular endothelial HO-1 staining tau pom, thaum kuaj pom muaj qhov zoo ntawm podocytes [27]. Txog thaum tsis ntev los no hauv HUS ib txwm, txawm tias hemolysis hauv cov kab mob no qhia txog kev koom tes ntawm heme thiab HO-1, cov ntaub ntawv tsis tshua muaj. Tsuas yog ib tsab xov xwm qhia tias Shiga-zoo li co toxins (Stx), secreted los ntawm E. Coli, tuaj yeem inhibit HO-1 qhia hauv lub raum epithelial hlwb [142]. Txawm li cas los xij, ib tsab xov xwm tsis ntev los no tau tshaj tawm qhov tseem ceeb ntawm qib plasma heme hauv cov neeg mob STEC-HUS piv nrog cov kev tswj hwm, sib cuam tshuam nrog cov qib ntshav hemopexin qis tab sis muaj feem cuam tshuam nrog cov qib ntshav siab ntawm HO-1 [64]. Ntxiv mus, microvascular glomerular EC tau incubated nrog heme upregulated HO-1 qhia ywj siab ntawm muaj STx.
Lub peev xwm ntawm glomerular EC los tswj hwm HO-1 tsis muaj zog dua li lwm hom EC [27]; Txawm li cas los xij, qhov txo qis ntawm HO-1 hauv glomerular EC tuaj yeem piav qhia lawv qhov kev cuam tshuam tshwj xeeb hauv HUS.
Malaria
Kev kis kab mob nrog cov kab mob Plasmodium yog lub luag haujlwm rau hemolysis nrog hemoglobin thiab tso tawm dawb heme. Mob hnyavraumKev raug mob yog qhov chaw kho mob ntawm tus kab mob hnyav thiab malaria kuj tseem cuam tshuam nrog kev sib tsoo glomerupathies [143]. Labile heme concentrations yog nce nyob rau hauv plasma ntawm cov neeg mob thiab nyob rau hauv nas qauv; interestingly, labile heme theem nyob rau hauv lub tom kawg tau nce ntau zog nyob rau hauv cov zis piv rau plasma [144]. HO-1 kev qhia tau pom tias muaj kev tiv thaiv hauv cov kab mob malaria nas qauv ntawm P. berghei ANKA ntawm CO tiam uas, vim nws khi rau hemoglobin, tiv thaiv nws cov oxidation thiab tiam ntawm dawb heme [145]. Malaria yog txuam nrog HO-1 upregulation nyob rau hauv proximal tubular epithelial hlwb nyob rau hauv tib lub qauv, thiab nyob rau hauv ib tug Plasmodium chabaudi chabaudi nas qauv [144,146]. Hauv cov qauv tom kawg, HO-1-/- nas muaj qhov sib thooj ntawm tubular necrosis nrog hemoglobin casts thiab cov txiaj ntsig zoo ntawm HO-1 kev qhia rau kev ciaj sia nyob ntawm nws qhov tshwj xeeb ze ze tubular qhov chaw (raws li kev tawm tsam rau lub siab, endothelial lossis cerebral expression) thiab yog Nrf2-dependant [144].HO-1 upregulation nyob rau hauv tubular epithelial hlwb li no zoo li reno-tiv thaiv nyob rau hauv cov ntsiab lus ntawm malaria.
Paroxysmal Nocturne hemoglobinuria
Paroxysmal nocturne hemoglobinuria (PNH) is an acquired clonal defect of phosphatidylinositol glycan anchor synthesis, responsible for enhanced RBC susceptibility to hemolysis [147]. PNH has been associated not only with AKI [148–152] but also with CKD (risk increased >6 ib.) [153]. Interestingly, ntxiv inhibition los ntawm Eculizumab
txhim kho lub raum ua haujlwm hauv txhua theem ntawm CKD (hauv 6 lub hlis). Cov txheej txheem tau npaj rau kev txhim kho zoo li no yog kev kho dua tshiab ntawm TSIS muaj nyob thiab tom qab hloov pauv hauv lub raum vascular tone. Kev nthuav qhia ntau ntxiv ntawm HO-1 tau tshaj tawm hauv cortex thiab sab nraud medulla tubular EC thiab macrophages (tseem ceeb hauv thaj chaw hemosiderin-nplua nuj) [154,155]; Hauv vitro, txhim kho kev qhia ntawm HO-1 tau pom thaum lub raum tubular epithelial hlwb raug nthuav tawm rau PNH cov neeg mob cov zis [155]. Txawm li cas los xij, lub luag haujlwm ntawm qhov txhim kho HO-1 qhia hauv PNH cov neeg mob'lub raumxav tau kev kawm ntxiv, tshwj xeeb, piv txwv li, hauv kev sib raug zoo nrog cov ntaub ntawv kho mob txograumkev ua haujlwm thiab cov teebmeem ntawm kev ua kom tiav inhibition.
4.1.2. Rhabdomyolysis
Rhabdomyolysis yog ib qho mob pob txha loj heev ntawm ntau yam etiology, tshwj xeeb tshaj yog kev raug mob ("crush syndrome"), cov leeg nqaij hypoxia, caj ces tsis xws luag, tshuaj noj, lossis kev siv yeeb tshuaj [102]. Qhov kev puas tsuaj no yog lub luag haujlwm rau kev tso tawm ntau dhau mus rau hauv kev ncig ntawm cov ntsiab lus ntawm cov leeg nqaij, suav nrog electrolytes, myoglobin, thiab lwm yam sarcoplasmic proteins (creatine kinase, aldolase, thiab lwm yam). Myoglobin thiab nws cov pa oxygen carrier, heme, tshwj xeeb tshaj yog koom nrog hauv cov teeb meem uas ua rau muaj kev phom sij tshaj plaws ntawm rhabdomyolysis, mob hnyav.raumraug mob (RIAKI), lub luag hauj lwm rau ib qho tseem ceeb morbi-mortality nyob rau hauv intensive care units [156]. Cov txheej txheem rau kev raug mob raum tau piav qhia raws li kev sib koom ua ke ntawm lub raum vasoconstriction [157], proximal tubular aggression (los ntawm oxidative stress, lipid peroxidation [158,159], thiab macrophage activation [160,161]), thiab intra-tubular nag lossis daus ntawm myoglobin. Tsis ntev los no, qhov ntxiv tau raug tshaj tawm los ua lub luag haujlwm pabcuam-hauv ib feem ntawm kev ua raws li-hauv RIAKI [30,162].
Induction ntawm HO-1 qhia tau pom ze li ntawm 30 xyoo dhau los hauv cov qauv nas ntawm glycerol-induced rhabdomyolysis [34]. Hauv cov qauv no, ib qho kev txhaj tshuaj ntawm hemoglobin ua ntej qhov kev sib tw glycerol txhim kho HO-1 qhia tau txaus los tiv thaivraumtsis ua haujlwm, thiab kev tuag tau txo qis heev (los ntawm 100 feem pua mus rau 14 feem pua). Ntawm qhov tsis sib xws, kev sib tw inhibition ntawm HO-1 zoo li nce AKI: nyob rau tib lub glycerol nas qauv, HO-1 -/- nas muaj fulminant, irreversible lub raum tsis ua hauj lwm, thiab 100 feem pua kev tuag [112]. HO-1 kev qhia tau nce mus rau qhov siab tshaj plaws ntawm 48h tom qab txhaj tshuaj glycerol thiab tom qab ntawd txo qis, qhov kev txo qis hauv kev tiv thaiv kev tiv thaiv kab mob tshwm sim [163]. HO-1 qhia hauv lubraumHauv kev teb rau kev sib tw glycerol tshwj xeeb tshaj yog nyob rau hauv kev sib piv nrog rau lwm cov qauv ntawm AKI (xws li ureteral obstruction, cisplatin, ischemic / reperfusion raug mob), raws li plasmatic concentration thiab intrarenal HO-1 protein thiab mRNA mus txog qib siab tshaj plaws hauv cov qauv no [ 164, 165] ib. Upregulation ntawm HO-1 qhia los ntawm pyruvate (ib tug hydrogen peroxide scavenger) ua ntej glycerol txhaj yog txuam nrog raum tiv thaiv RIAKI [166], tab sis kuj nce lub raum qabzib concentrations thiab IL-10 mRNAs, thaum txo monocyte. chemoattractant protein 1 (MCP-1) thiab qog necrosis factor (TNF-a) [167]. Qhov no qhia txog lub luag haujlwm tiv thaiv kab mob ntawm HO-1 hauv RIAKI. Txawm li cas los xij, lub luag haujlwm cytoprotective rau HO-1 hauvraumtsis txaus rau nws tiv thaiv RIAKI; Piv txwv li, txawm hais tias muaj kev qhia ntau dua ntawm HO-1, nas tsis muaj cov saw hnyav ferritin muaj qhov tshwm sim hnyav dua tom qab txhaj tshuaj glycerol [168]. HO-1 yog li no tuaj yeem ua lub luag haujlwm tsis zoo, tus neeg saib xyuas txij li HO-1 kev qhia tau pom tias tau hloov kho ib txhij nrog ferritin [34]. Ntawm qhov tod tes, HO-1 tsis yog ib leeg hauv kev them nyiaj cytoprotection hauv glycerol-induced RIAKI, raws li kev kho N-acetylcysteine (ib qho kev tshem tawm ntawm cov dawb radicals) kuj pom muaj txiaj ntsig zoo [169].
Tsis tas li ntawd, kev tiv thaiv HO-1 induction, ua ke nrog induction ntawm lwm yam tshuaj tiv thaiv kab mob thiab cytoprotective stress proteins xws li ferritin, haptoglobin, hemopexin, alpha 1 antitrypsin, thiab IL-10, tau raug qhia kom yuav. tiv thaiv cov teebmeem, tshwj xeeb hauv glycerol-induced RIAKI qauv. Qhov no feem ntau hu ua "kev kho mob ua ntej" hauv cov ntaub ntawv. Piv txwv li, infusion ntawm nitrated myoglobin los yog SnPP ua lub luag haujlwm sib koom ua ke hauv HO-1 induction, yog li khaws cia lub raum ua haujlwm [170]. Cov tshuaj anticholinergic Penehyclidine hydrochloride (PHC) [171], tab sis kuj muaj curcumin (polyphenol nrog antioxidant, anti-apoptotic thiab anti-inflammatory zog) [172,173], ob leeg tau qhia rau
ua kom muaj kev tiv thaiv ntawm glycerol-induced AKI thaum tseem txo cov cell apoptosis hauv lub raum cov ntaub so ntswg, txhim kho Nrf2 activation thiab HO-1 induction.
Interestingly, heme receptor TLR4 tej zaum yuav tsis cuam tshuam rau cov teebmeem tshwm sim, txij li TLR4-/- nas tsis tau tiv thaiv glycerol-induced RIAKI, thiab TLR4 inhibitor TAK-242 ua tsis tiavraumua haujlwm txawm tias khaws cov ntshav ntws [174]. Tsis tas li ntawd, HO-1 kev qhia hauv tubular hlwb hauv vitro tsis tau inhibited los ntawm TAK-242; qhov no qhia tias lwm cov heme receptors koom nrog HO-1 induction. Receptor rau qib siab glycation kawg-cov khoom lag luam (RAGE) kuj tau lees paub tias yog ib qho receptor rau heme [175] thiab tau qhia hauv tubular cells [176] - nws yuav txaus siab los tshawb txog nws lub luag haujlwm hauv RIAKI. Kev nthuav qhia ntawm HO-1 tau tshaj tawm tias tsis muaj kev ywj pheej ntawm kev ua kom muaj zog ntxiv hauv RIAKI, txij li HO-1 tau hloov kho sib npaug ntawm ob hom tsiaj qus thiab C3-/- nas txhaj nrog glycerol, txawm tias txo qisraumkab mob hauv C3-/- nas [30].
Thaum kawg, HO-1 muaj lub luag haujlwm tiv thaiv feem ntau los ntawm kev txhim kho lub raum microcirculation, txo cov kev ntxhov siab oxidative, thiab tej zaum kuj yog los ntawm kev tswj lub cev tiv thaiv kab mob hauv RIAKI. Lub luag haujlwm tiv thaiv no, txawm li cas los xij, tsis txaus los ntawm nws tus kheej los tiv thaiv tag nrhoraumlos ntawm RIAKI lesions.
4.2. Kab mob uas tsis muaj Cell-Free Heme tso tawm
Cov kab mob no suav nrog ntau yam pathologies cuam tshuam rau lub cevraumuas tsis yog classically txuam nrog loj heme tso tawm, thiab, raws li lub hom phiaj ntawm qhov kev tshuaj xyuas no, peb yuav nthuav qhia ntau yam pathologies uas HO-1 lub luag hauj lwm tau elicited kev tshawb fawb txaus siab. Peb lub hom phiaj yog txhawm rau txheeb xyuas seb HO-1 kev qhia tau cuam tshuam li cas nrog cov kab mob physiopathology uas tsis tshua muaj tshwm sim tshwj tsis yog lub raum puas ntau dua li ua kom tag nrho. Xwb, HO-1 tau koom nrog toxicity (gentamycin, cisplatin, calcineurin inhibitor, radiocontrast khoom, mercuric chloride), septic, mechanic (obstruction), hemodynamic (hypertension, ischemia-reperfusion), metabolic (diabetes), genetic. (PolycysticLub raumKab mob (PKD)) thiab raum tshwj xeeb (membranous nephropathies, anti-GBM) thiab kab mob (Lupus nephropathy) immunologic pathologies (Table 1). Ntxiv mus, cov kab mob no cuam tshuam rau cov kab mob podocytes, mesangial, tubular epithelial, endothelial, thiab interstitial hlwb nyob rau hauv ntau txoj kev, yog li qhia txog cov teebmeem pleiotropic ntawm HO-1 hauv ob qho tib si physiology thiab kab mob. Thaum kawg, HO-1 tau koom nrog rau theem mob ntawm lub raum raug mob, tab sis kuj nyob rau theem mob ntawm lub raum puas. Peb tau xaiv los tsom mus rau kev txiav txim siab HO-1 lub luag haujlwm hauv pathologies uas yog cov ntsiab lus ntawm lub cev tseem ceeb ntawm cov ntaub ntawv lossis cov khoom ntawm kev sim tshuaj txog HO-1 (nrog rau kev zam ntawm preeclampsia thiab PKD, uas cov ntaub ntawv tseem tsis tshua muaj). Kev tiv thaiv kev ua haujlwm ntawm HO-1 hauv lwm cov kab mob, uas los ntawm cov ntaub ntawv tuaj yeem tseem ceeb ib yam li cov uas tam sim no yog qhov kev sim tshuaj ntsuam xyuas, yuav raug sau tseg hauv Table 1 thiab cov kev cia siab kho mob yav tom ntej txog cov no yuav tau tham nyob rau tom ntej. ntu.
txhim kho kev kho mob, tshwj xeeb tshaj yog rau cov kev cuam tshuam uas tau teem tseg (tsawg kawg ib nrab), xws li kev phais plawv lossis kev hloov pauv.
4.2.2. Sepsis
Sepsis-associated AKI (S-AKI) yog ib qho teeb meem nquag hauv cov neeg mob hnyav thiab cuam tshuam nrog kev mob thiab kev tuag [291]. Sepsis muaj ib qho nyuaj thiab tshwj xeeb pathophysiology, tsis to taub tag, uas txawv nws los ntawm lwm yam AKI phenotypes. Yog tias S-AKI yav dhau los tau suav tias tsuas yog kev hloov pauv ntawm lub raum los ntawm kev txo qis hauv lub raum mus rau tubular epithelial cell tuag (los yog mob tubular necrosis), qhov kev txhais dav dav niaj hnub no suav nrog microvascular dysfunction, inflammation, thiab metabolic reprogram-ming [291,292]. Kev tiv thaiv thiab kev kam rau siab tau pom tias yog ob qho kev sib txawv uas khaws ciaraumkev ua haujlwm thiab txhawb nqa qhov txhab kho thaum lub sijhawm sepsis [293]. Lipopolysaccharide (LPS) tau paub tias ua rau HO-1 qhia tau yuav luag 50 xyoo [294]. Nws tau txhais tias HO-1 confers tshwj xeebraumtiv thaiv LPS vim HO-1-/- nas pom qhov txo qis hauv GFR thiab lub raum cov ntshav ntws, nce lub raum cytokine qhia, thiab nce kev ua kom NF-kB tom qab LPS txhaj [279]. Hauv cov qauv ntawm polymicrobial sepsis (cecal ligation thiab puncture), HO-1-cov nas tsis muaj peev xwm pom tau tias muaj kev tuag ntau dua [280] tab sis kuj nce ntshav Urea Nitrogen (BUN) qib thiab tubular epithelial necrosis [105]. Qib ntawm plasmatic, cell-free heme tau nce siab tom qab qib siab kis kab mob thaum kho hemopexin txo qis kev tuag thiab txhim kho.raummuaj nuj nqi (tshwj xeeb txhim kho BUN qib), yog li qhia txog kev ua haujlwm ntawm heme-dependent lub luag haujlwm rau cov txiaj ntsig tau pom [105]. Txhim kho HO-1 kev qhia, thiab tshwj xeeb tshaj yog nws lub peev xwm rau CO tsim hauv macrophages, tau tshaj tawm tias yog qhov tseem ceeb rau kev tshem tawm cov kab mob thiab ua rau lub raum tiv thaiv AKI [281].
Noj ua ke, HO-1 kev qhia, uas yog txhim kho los ntawm endotoxins thiab tej zaum los ntawm kev nce heme theem thaum lub sij hawm sepsis, yog ib qho tseem ceeb nyob rau hauv lub raum tsis kam mus rau pathogen-induced tubular epithelial necrosis tab sis kuj feem ntau rau kev tshem tawm cov kab mob ntawm tag nrho- lub cev theem.
4.2.3. Hypertensive nephropathy
Kev kub siab yog thawj zaug lossis thib ob ua rau mob CKD (nyob ntawm thaj chaw nyob) thiab yog ib qho tseem ceeb tshaj plaws thiab nquag ua rau mob raum. Thaum mob ntshav siab, lub luag haujlwm ntawm Angiotensin II (Ang II) yog qhov tseem ceeb, dhau li nws lub luag haujlwm hemodynamic, thiab tau koom nrog hauv cov qauv tsiaj nrog podocyte poob [295], txhim kho kev tsim cov matrix los ntawm cov hlwb mesangial [296], thiab glomerulosclerosis, tab sis kuj. nrog rau kev hloov pauv hauv kev nthuav qhia hauv lub tubule [297] thiab interstitial fibrosis [298], nrog rau oxidative kev nyuaj siab thiab mob [299].
Hauv cov tsiaj, HO-1-/- nas tau tshaj tawm tias muaj ntshav siab tib yam li kev tswj xyuas qhia tias HO-1 tsis koom nrog kev saib xyuas ntshav siab hauv lub cev [261]; Txawm li cas los xij, unilateralraumclamping nyob rau hauv HO-1-/- tsiaj induced mob siab heev thiab plawv hypertrophy tshaj nyob rau hauv heterozygous los yog HO-1 ntxiv / ntxiv nas, nrog nws kim heev ischemic raug mob ntawm lub corticomedullary hlws ris [261]. Infusion ntawm Angiotensin II (Ang II) nce HO-1 mRNA ntau ntau thiab nws cov lus qhia hauv adventitial thiab endothelial hlwb hauv Ang II-induced, hypertensive rat aortas, tab sis losartan lossis hydralazine kev kho mob tiv thaiv ob qho tib si Ang II induction ntawm kub siab thiab upregulation ntawm HO-1 expression [262]. Kev nthuav tawm ntau dhau ntawm HO-1, thiab cov cim ntxiv ntawm CO, tau pom tias txo cov teebmeem ntawm Ang II ntawm ntshav siab [263]. HO-1 -/- nas kuj tau nce ntshav siab piv nrog HO ntxiv / ntxiv tom qab Ang II infusion, thiab qhov no tau cuam tshuam nrog endothelial inflammation hauv vivo, thiab nrog aortic infiltration ntawm pro-inflammatory monocytes thiab neutrophils [264]. Cov txiaj ntsig ntawm Ang II ntawm HO-1 tau raug qhia kom kho los ntawm Angiotensin Receptor 1 (AT1) [265].
Kev tswj hwm Heme, uas ua rau kom lub raum HO-1 qhia, txo cov ntshav siab nyob rau hauv cov nas hypertensive, ob qho tib si thaum ua ke nrog kev tswj hwm ntawm arginine [266] lossis ntawm nws tus kheej [267]. Cov teebmeem ntawm heme ntawm cov ntshav siab tau cuam tshuam los ntawm kev tswj hwm ntawm HO-1 inhibitor ZnPP [267].
Lub medullar qhia ntawm HO-1 tau rov tshawb nrhiav: qhov tseeb, medullary interstitial infusion ntawm HO-1 inhibitor zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG - los ntawm kev sojntsuam intramedullary dialysis) txo qis. medullar ntshav ntws thiab qhia txog lub luag haujlwm tseem ceeb rau HO-1 hauv nws txoj kev tu [25]. Ntawm qhov tod tes, medullary infusion ntawm CoPP, lub zog HO-1 inductor, khaws cia uni-nephrectomized nas los ntawm Ang II-dependent hypertension [268]. Ntau tus qauv ntawm HO-1- tshwj xeeb tshaj tawm hauv TALH tau tsim thiab tau qhia txog lub luag haujlwm tshwj xeeb rau HO-1 txog kev tiv thaiv TALH hlwb los ntawm Ang II (tseem ceeb txo qis prostaglandin E2 (PGE2) qib thiab Ang II- induced DNA puas) [269] thiab txo cov ntshav siab, tab sis kuj txo medullary Na-K-Cl cotransporter 2 (NKCC2) transporter qhia thiab sensibility rau furosemide [270], yog li modulating natriuresis raws li yav tas los qhia [271].
Hauv kev xaus, yog tias HO-1 tsis yog qhov tseem ceeb los khaws cov ntshav siab hauv lub cev, txawm li cas los xij nws muaj lub luag haujlwm tseem ceeb hauv kev txo cov ntshav siab hauv cov kab mob pathological, tshwj xeeb hauv kev nce hauv Ang II. Tsis tas li ntawd, medullar thiab, tshwj xeeb tshaj yog, TALH qhia ntawm HO-1 zoo li cuam tshuam ntau yam cuam tshuam rau cov kab mob vascular nephropathies, xws li txo qis ntshav thiab natriuresis, yog li ua rau nws tsim nyog los ua lub hom phiaj rau kev kho mob yav tom ntej.
4.2.4 ib. Mob ntshav qab zib nephropathy
Mob ntshav qab zib nephropathy (DN), uas yog ib qho teeb meem loj ntawm microangiopathic mob ntshav qab zib, tau piav qhia los ntawm qhov tshwm sim ntawm cov mob hyperglycemia thiab tsub zuj zuj ntawm cov khoom lag luam qib siab glycated [300], podocyte poob [301], txhim kho oxidative kev nyuaj siab [302], thiab cuam tshuam. microcirculation [303], orchestrated notably by innate immunity [304] ua rau fibrosis, matrix deposition, thiab mob raum mob [305].
Glomerular HO-1 qhia, uas tsis muaj zog nyob rau hauv feem ntau ntawm cov kab mob raum, tau poob nthav tau tshaj tawm raws li kev nce hauv ntau hom tsiaj mob ntshav qab zib xws li streptozotocin (STZ)-induced diabetes mellitus [72,187,188], thiab hauv cov qauv caj ces. dB/db nas [189]. Txawm tias ib feem ntawm caj ces tsis txaus nyob rau hauv HO-1 yog txaus rau sensitize nas mus rau kev loj hlob ntawm cov ntshav qab zib glomerular microvascular lesions [190]. Hauv vitro, cov piam thaj ntau ntxiv tau nce HO-1 qhia hauv podocytes, thiab lawv cov apoptosis. HO-1 inhibition (los ntawm ZnPP lossis HO-1 siRNA) nce tus naj npawb ntawm apoptotic podocytes ob qho tib si hauv vitro thiab hauv vivo, rov hais txog lub luag haujlwm tiv thaiv HO-1 [72]. Cov teebmeem ntawm HO-1 induction los ntawm CoPP ntawm apoptosis thiab glomerular raug mob tau raug lees paub nyob rau hauv tus qauv ntawm STZ-kho, spontaneously hypertensive nas (SHR), uas pom tau tias txo qis NF-kB-induced inflammation thiab oxidative stress [191].
Lub luag haujlwm tiv thaiv ntawm HO-1 hauv DN cuam tshuam tsis yog podocytes nkaus xwb tab sis kuj tseem muaj cov hlwb mesangial, los ntawm kev cuam tshuam ntawm Nrf2 [192]. Mouse mesangial cells overexpressing Nrf2 thiab raug cov piam thaj siab tau pom cov kev qhia tawm ntawm HO-1, nrog rau kev txo qis ROS ntau lawm thiab cell proliferation. Cov kev soj ntsuam no tau lees paub los ntawm kev sim nrog Nrf2-cov nas uas tawm tsam qhov sib txawv.
Enhanced HO-1 qhia kuj plays lub luag hauj lwm nyob rau hauv lub raum hemodynamics, raws li qhia nyob rau hauv STZ- kho nas uas tau txais CoPP, los ntawm upregulation ntawm extracellular superoxide dismutase (SOD) thiab endothelial Nitric-oxide Synthase (NOS) ua rau endothelial so thiab txo. ROS ntau lawm [193]. Tsis tas li ntawd, HO-1 inhibition los ntawm SnMP nce lub raum vascular tsis kam thiab hloov GFR thiab lub raum cov ntshav ntws, thiab cov nyhuv no tau thim rov qab los ntawm kev sib koom ua ke ntawm SOD mimetic lossis CO-tso molecule [194].
Thaum kawg, HO-1 kuj tseem ua lub luag haujlwm hauv insulin rhiab heev: nws qhov kev txhim kho tuaj yeem txo cov ntaub so ntswg adipose thiab ua rau kev hloov pauv ntawm cov ntaub so ntswg adipose hauv cov kab mob ntshav qab zib mellitus qauv ntawm kev rog-insulin resistance [195]. Hauv cov neeg mob ntshav qab zib hom 2 uas muaj kev tswj glycemic tsis zoo, T(-413)A SNP hauv HO-1 tus txhawb nqa tau cuam tshuam nrog kev txhim kho albuminuria [196], tab sis cov kev tshawb fawb loj dua yuav tsum tau lees paub cov txiaj ntsig no.
Ntawm HO-1 inducers, hemin tau raug tshuaj xyuas zoo hauv kev tswj hwm nrog STZ thiab tau cuam tshuam nrog HO-1 cov lus qhia, tshwj xeeb tshaj yog nyob rau hauv tubules, uas nthuav tau cuam tshuam nrog kev txhim kho lub raum ua haujlwm, txo qis inducible NOS. (iNOS), ntshav qabzib, micro-albuminuria, glomerulosclerosis, thiab fibrosis ntawm 60 hnub [197]. Cov kev soj ntsuam no qhia ntxiv hais txog crosstalk ntawm glomeruli thiab tubules txog HO-1. Hemin tau raug npaj los ua los ntawm kev xaiv kev txhim kho ntawm kev tiv thaiv kab mob macrophage-M2 phenotype thiab IL-10, tom qab kev tshawb fawb inhibiting pro-inflammatory macrophage-M1 phenotype thiab suppressing extracellular matrix/profbrotic yam ua lub luag haujlwm rau lub raum kab mob thiab interstitial macrophage infiltration hauv STZ ND nas [198]. Hemin kuj tseem tuaj yeem tiv thaiv kev ua haujlwm ntawm endothelium los ntawm kev sib txuas ntawm bilirubin, raws li tau hais tseg hauv db / db genetic mouse qauv ntawm ntshav qab zib qhov twg hemin thiab bilirubin tau tshaj tawm, zoo ib yam li endothelium-mediated so ntawm aortas [189]. Ob peb lwm HO-1 inducers, uas yog, sinapic acid [199], artemisinin [200], thiab puerarin [201], tshaj tawm tias txo qis.raumkev raug mob hauv STZ-kho nas nas, muab qhov ua tau ntawm kev kho tshiab.
Raws li tau hais los saum toj no, HO-1 tsis yog HO nkaus xwb cuam tshuam rau kev tiv thaiv kab mob ntshav qab zib nephropathy, thiab HO-2 tsis txaus tau pom tias txhim kho STZ-vim lub raum tsis ua haujlwm thiab raug mob, thaum HO{{3} } upregulation tiv thaiv cov teebmeem tsis zoo ntawm DN [306].
Txhawm rau xaus, HO-1 ua lub luag haujlwm ntau yam thiab tsis xav txog hauv DN los ntawm kev txwv apoptosis ntawm podocytes thiab mesangial proliferation, modulating raum hemodynamics, thiab txhawb kev nkag siab ntawm insulin, tab sis nws kuj tseem tuaj yeem cuam tshuam glomerulo-tubular crosstalk hauv heme-dependent. .
4.2.5. Mob raum mob
Thaum HO-1 muaj lub luag haujlwm pleiotropic hauv cov nephropathies tshwj xeeb, cov no tsis ntxiv rau tag nrho cov paubraumpathologies. Tseeb tiag, txhua yam ntawm pathologies tau piav qhia yav dhau los hauv ntu no, nrog rau ntau yam tsis tau hais txog ntawm no, tuaj yeem ua rau muaj kev loj hlob thiab kev tuag ntawm lub raum mus tas li thiab hloov pauv cov haujlwm nephrons nrog interstitial fibrosis yam ntxwv ntawm cov mob ntev.raumkab mob (CKD). Unilateral ureteral obstruction (UUO) yog tus qauv kub tus qauv nas rau kev kawm nrawm, nce qib interstitial fibrosis [272]. Thaum ntxov HO-1 qhia tau pom nyob rau hauv peri-glomerular thiab peritubular interstitium [273]. Interestingly, kev tiv thaiv kev txhim kho ntawm HO-1 qhia los ntawm hemin 48h ua ntej UUO attenuated fibrosis hauv nas los ntawm down-regulating inflammatory thiab pro-brotic genes, thiab txo cov pro-apoptotic pathways (caspase-3 activation thiab protein ntau), lub raum tsis ua haujlwm [274,275]; ZnPP (ib qho HO-1 inhibitor) tiv thaiv cov teebmeem tiv thaiv no. Kev lees paub lub luag haujlwm tiv thaiv no, HO-1 -/- nas nrog UUO nthuav tawm nce fibrosis, tubular TGF-ß1 qhia, thiab o, thiab tau txhim kho epithelial mus rau mesenchymal hloov nrog nce infilltration ntawm macrophages [276], nrog rau kev nthuav qhia ntxiv. ntawm M2 cov cim thiab hnyav-chain ferritin H [277]. HO-1 overexpression nyob rau hauv cov nas transgenic tau tshaj tawm kom txo tau lub raum interstitial fibrosis, inhibit qhov poob ntawm peritubular capillaries, suppress activation thiab proliferation ntawm myofibroblasts, txwv tsis pub tubule-interstitial infiltration ntawm macrophages hauv kev tswj hwm thiab kev tswj hwm kev tswj hwm. mus [278]. Ua ke, cov kev tshawb fawb no qhia txog lub luag haujlwm pleiotropic rau HO-1 hauv kev nrawm nrawm, cuam tshuam los ntawm fibrosis, txwv cov macrophage infiltration thaum sib tham txog lawv cov kev tswj hwm phenotype, txhawb kev tu microcirculation thiab inhibiting pro-fibrotic txheej txheem. Nws yog, yog li ntawd, tsis xav tsis thoob tias muaj kev txaus siab ntau ntxiv hauv HO-1-cov phiaj xwm kho mob los kho cov kab mob nrawm nrawm.
Ntawm cov kev saib xyuas tseem ceeb tseem ceeb thaum lub sij hawm CKD yog cov khoom pov tseg hauv metabolic thiab co toxins, uas cov nephrons nyob rau thaum kawg tsis tuaj yeem tshem tawm. Ntawm lawv, indoxyl sulfate, uremic toxin, tau pom tias yuav txo qis lub raum qhia ntawm Nrf2 los ntawm kev ua kom NF-kB, yog li txo qis- tswj HO-1 thiab NQO1 thiab nce kev tsim tawm ntawm ROS [307]. Tseeb tiag, qhov tsis zoo HO-1 upregulation tau piav qhia nyob rau hauv tus qauv nas ntawm kev mob tshwm sim tom qab ischemic o [308], thaum txo qis Nrf2 qhia (HO-1 qhov kev hloov pauv) kuj tau tshaj tawm hauv lwm tus qauv nas ntawm CKD [309,310] tom qab kev tswj hwm ntawm Nrf2 repressor Keap1. Qhov kev tswj tsis tau zoo ntawm HO-1 kuj tau tshaj tawm hauv cov neeg mob, nrog rau qhov tseem ceeb ntawm kev tswj hwm ntawm plasmatic HO-1 tom qab kev tswj hwm ntawm qis qis ntawm SNPP hauv cov neeg mob CKD piv rau cov neeg ua haujlwm noj qab haus huv [311].
Interestingly, ntawm cov neeg mob uas muaj kab mob plawv, ntau dua ntawm GT dinucleotide rov ua dua hauv HMOX1 gene txhawb nqa, txo nws txoj kev qhia, tau cuam tshuam nrog kev pheej hmoo ntawm CKD [312]. Yog li, qhov tsis ua haujlwm ntawm cov enzymes tiv thaiv kab mob xws li HO-1 yuav raug kho tuaj yeem ua rau muaj kev ntxhov siab oxidative thiab o, uas tuaj yeem ua rau muaj kev tiv thaiv tus kheej, txhawb kev raug mob [308]. Txawm hais tias muaj kev cuam tshuam cov pa oxygen hauv CKD, HIF tsis raug tswj xyuas thiab tau tshaj tawm tias tau koom nrog hauv HO-1 downregulation: HIF induction nyob rau hauv tus qauv nas ntawm CKD rov qab HO-1 qhia, ua ke nrog VEGF thiab angiogenesis [313]. Thaum kawg, HO-1 nyob rau hauv cov tubule proximal yuav txo tau cov albumin-stimulated zus tau tej cov cytokines xws li MCP-1 [314]. Yog li, kev tsim txom ntawm HO-1 qhia los ntawm Nrf2 lossis HIF zoo li koom nrog CKD kev loj hlob los ntawm kev tsis txaus siab cuam tshuam rau angiogenesis thiab proteinuria.
Txhawm rau xaus, qhov tsis txaus ntawm HO-1 kev tswj hwm thaum lub sij hawm CKD tuaj yeem pom zoo rau fibrosis, tshwj xeeb tshaj yog los ntawm kev txo qis angiogenesis thiab tsim thiab tswj lub xeev pro-inflammatory tshwj xeeb yog hais txog macrophage phenotype.
5. Modulation ntawm HO-1 Axis: Cov tswv yim yav dhau los, tam sim no thiab yav tom ntej
Cov ntaub ntawv pov thawj ntawm kev noj qab haus huv ntawm HO-1 thiab nws txoj kev koom tes hauvraumCov kab mob tau sib sau ua ke thiab tau txhawb ntau tus kws tshawb fawb los tshawb xyuas nws ua lub hom phiaj kho mob. Txawm hais tias qhov no tau ua rau qee cov lus qhia txog kev kho mob, tsis muaj cov tshuaj tsom mus rau HO system tseem tau muab txhais rau hauv tsev kho mob xyaum. Qhov nyuaj ntawm cov txheej txheem kab mob tau kawm, thiab qee zaum cuam tshuam los ntawm cov qauv tsiaj, ua rau muaj teeb meem hauv nws daim ntawv thov kev kho mob. Hauv seem no, peb yuav piav qhia luv luv txog kev sim tshuaj tib neeg tsis ntev los no thiab tsis tu ncua, ua ntej sib tham txog qee qhov teeb meem uas HO-1 tej zaum yuav yog txoj kev kho mob zoo.
5.1. Yav dhau los thiab tam sim no kev sim tshuaj nyob rau hauv tib neeg
Nyob rau hauv cov ntsiab lus ntawm ib tug mob tshwm sim ntau tshaj cov kev cai systems, free heme yog tsis muaj dab tsi. Txawm li cas los xij, heme kuj yog ib qho ntawm cov inducers tseem ceeb ntawm HO-1. Yog li, HO-1 upregulation los ntawm kev tswj hwm ntawm cov tshuaj tsawg ntawm heme (los yog lwm yam HO-1 inducer) tuaj yeem ua rau muaj txiaj ntsig zoo los ntawm kev tsim cov tshuaj antioxidant thiab cytoprotective metabolites. Kev tswj hwm ntawm heme raws li HO-1 inducer tau raug suav tias yog txoj hauv kev kho mob thiab, raws li tau piav qhia saum toj no, kev kho mob ua ntej nrog cov koob tshuaj tsawg ntawm heme hauv cov qauv tsiaj sib txawv ntawmraumKab mob tau cuam tshuam nrog kev txo qis hauv qhov mob, oxidative kev nyuaj siab, thiab cov ntaub so ntswg puas [315-317]. Hauv tib neeg, ob qho tib si heme thiab heme arginate (tus neeg sawv cev kho mob rau porphyria) ua rau HO-1 qhia hauv cov neeg ua haujlwm noj qab haus huv [318,319], thaum heme arginate txhim kho kev sim ischemia-reperfusion lesions hauv cov neeg noj qab haus huv [320]. Cov ntaub ntawv no tau tsa kev cia siab rau kev siv tshuaj kho mob ntawm HO-1 induction siv heme. Txawm li cas los xij, hemin (cov ntaub ntawv oxidized ntawm heme) kev kho mob tsis yog yam tsis muaj kev phom sij: tom qab kev tswj hwm ntawm hemin hauv cov neeg noj qab haus huv, thrombophlebitis tshwm sim hauv 45 feem pua ntawm cov neeg mob (4/9 cov neeg mob) [321]. Cov teeb meem thrombotic kuj tau piav qhia nyob rau hauv cov neeg mob uas muaj kev sib kis mob porphyria kho nrog hemin infusion. Muaj ob peb txoj kev tshawb fawb txog kev ua tau zoo thiab lawv cov txiaj ntsig tsis muaj tseeb. Hauv kev tshawb fawb ntawm cov neeg mob metabolic syndrome, heme arginate tsis txhim kho endothelial kev ua haujlwm lossis insulin rhiab heev, tab sis txo qis vasodilatory teb rau nitroglycerin [322]. Cov txiaj ntsig tsis zoo no sib piv nrog cov ntaub ntawv preclinical, tejzaum nws yog vim lub sijhawm luv ntawm kev kho mob thiab txwv tsis pub muaj kev cuam tshuam ntawm HO-1, nrog rau kev cuam tshuam ntawm cov qib siab plasma heme [322]. Cov kev tshawb fawb yav tom ntej yuav tsum tsom tsis yog tsuas yog txiav txim siab txog qhov muaj txiaj ntsig zoo thiab nws lub sijhawm tab sis kuj piav qhia tag nrho cov xwm txheej tshwj xeeb raws li qhov normalization ntawm cov ntshav plasma heme ua tiav. Lwm cov molecules, xws li statins [323,324] thiab 5-aminosalicylic acid [325], ua rau muaj kev tswj hwm zoo ntawm HO-1. Kev sim tshuaj ntsuam xyuas hauv SCD cov pej xeem los ntsuas qhov cuam tshuam ntawm atorvastatin ntawm kev ua haujlwm endothelial thiab cov kab mob ua paug thiab oxidative kev ntxhov siab, suav nrog HO-1 kev ua, tab tom ua (Table 2).
Lub paucity ntawm kev sim tshuaj tsom rau HO-1 hauv tib neeg yog qhov tseem ceeb thiab Table 2 qhia txog cov kev sim uas tam sim no hais txog ntawm ClinicalTrials.gov lub vev xaib. Kev tshawb nrhiav siv cov ntsiab lus "heme-oxygenase-1" THIAB "raum" tau txheeb xyuas tsuas yog 15 qhov kev sim tshuaj, peb ntawm cov uas tsis tau hloov kho lawv cov xwm txheej hauv ntau dua ob xyoos, txawm tias lawv hnub ua tiav tau dhau los thiab yog li tsis suav nrog hauv Table 2.
5.2. Kev nyuaj siab kho mob
Qhov tsis txaus ntseeg ntawm qhov ntsuas ntawm kev tshawb fawb txaus siab hauv HO-1 induction - ob qho tib si hauv vitro thiab hauv vivo - thiab qee qhov kev sim tshuaj tsis tu ncua yog qhov zoo kawg. Tseeb tiag, ntau qhov chaw grey tseem nyob ntawm qhov tshwm sim ntawm HO-1 induction, cuam tshuam kev hloov pauv ntawm vivo kev sim mus rau kev sim tshuaj. Qhov cuam tshuam ntev ntawm HO-1 induction hauv cov ntaub so ntswg thiab hlwb tsis to taub thiab tuaj yeem muaj kev cuam tshuam txog, piv txwv li, tumorigenesis, kev kho mob rau mob qog noj ntshav, lossis, ntau dua, muaj kev cuam tshuam rau kev kis kab mob.
Tseeb, nyob rau hauv sib piv nrog rau tag nrho cov kev tiv thaiv los piav nyob rau hauvraumpathologies, HO-1 pro-survival zog txhawb kev mob qog noj ntshav [326]. Tseeb tiag, kev txhim kho HO-1 kev qhia tau raug cuam tshuam nrog cov qog loj hlob, aggressiveness, metastatic thiab angiogenic muaj peev xwm, tiv thaiv kev kho mob, qog kev khiav tawm, thiab kev tsis zoo [327]. Tsis tas li ntawd, HO-1 inhibition pom muaj txiaj ntsig hauv ntau tus qauv mob qog noj ntshav [328]. Txawm hais tias HO-1 lub luag haujlwm hauv kev mob qog noj ntshav yog zaum ob (ob qho tib si tiv thaiv thiab kev puas tsuaj), kev ua haujlwm ntev ntawm HO-1 tuaj yeem ua lub luag haujlwm hauv cov qog nqaij hlav los ntawm kev pab cov qog kom dim ntawm lub cev tiv thaiv kab mob, uas tseem yuav tau kawm kom raug.
HO-1 induction kuj tuaj yeem cuam tshuam qhov kev ua tau zoo ntawm kev kho mob qog noj ntshav, uas yuav tsum tau saib xyuas hauv cov kev tshawb fawb yav tom ntej. Piv txwv li, HO-1 induction tau kawm kom ntxaws los tiv thaiv cisplatin toxicity [8,23,94,202–204], uas tseem nquag ua rau mob hnyav.raumraug mob los ntawm glomerular, vascular, thiab tubular puas [329]. Cov molecules sib txawv uas nce HO-1 qhia tau raug kawm los tiv thaiv cisplatin-induced apoptosis thiab o nyob rau hauv lub raum ntawm nas los yog nas qauv: microRNA-140-5p [206], JQ1 [207], Ferrero L [ 208], zinc oxide nanoparticles [209], human growth factor [210], bardoxolone methyl [205] thiab capsaicin (ib qho tseem ceeb ntawm cov kua txob kua txob) [211] tau kawm txog qhov no. Hmoov tsis zoo, tsuas yog ob peb ntawm cov kab lus no tau tshaj tawm txog cov txiaj ntsig ntawm cov molecules ntawm proapoptotic, antitumoral kev txiav txim ntawm cisplatin ntawm cov qog hlwb [207], uas yog qhov cuam tshuam loj rau lawv siv hauv kev tawm tsam iatrogenic raum puas tsuaj rau cov neeg mob qog noj ntshav.
Thaum kawg, cov tshuaj tiv thaiv kab mob ntawm HO-1 hauv kev ncig thiab cov neeg nyob hauv monocytes thiab macrophages tuaj yeem cuam tshuam rau kev kis kab mob. Tseeb, tag nrho cov pathologies tau piav qhia ntawm no, txawm tias kho los ntawm heme los yog tsis, yog txuam nrog kev kis kab mob ntau ntxiv: hauv kev hloov pauv lossis kab mob autoimmune, nws yog ib feem ntawm kev tiv thaiv kab mob; nyob rau hauv mob ntev, heme-txog pathologies xws li PNH (xws li ua ntej kev kho mob los ntawm Eculizumab [330]), SCD, thiab lwm yam., cov kab mob rov tshwm sim yog qhov cim ntawm tus kab mob. HO-1 xav tias yog qhov tseem ceeb rau kev tiv thaiv cov ntaub so ntswg puas thaum kis kab mob; Txawm li cas los xij, lub luag haujlwm no yog ob qho - tshwj xeeb raws li hom kab mob, raws li tau piav qhia rau cov kab mob hauv lub cev [331] - thiab nws cov khoom tolerogenic tuaj yeem txo cov kab mob tshem tawm [332]. Tshawb nrhiav seb qhov kev tiv thaiv kab mob ntawm HO-1 tuaj yeem tiv thaiv kab mob li cas (tej zaum tsuas yog me ntsis), tshwj xeeb tshaj yog nyob rau lub sijhawm ntev HO-1 induction, yuav tsum tau soj ntsuam hauv kev tshawb fawb yav tom ntej los lav kev nyab xeeb ntawm xws li daim ntawv thov.
Yog li, thaum nyob rau hauv vitro thiab hauv vivo cov ntaub ntawv qhia tau hais tias cov txiaj ntsig tau zoo hauv ob pebraumpathologies, cov ntaub ntawv ntau ntxiv ntawm qhov muaj peev xwm los ntawm cov neeg tuaj saib ntawm lub sijhawm ntev HO-1 induction yog xav tau los txhim kho peb txoj kev nkag siab txog yuav ua li cas HO-1 tuaj yeem raug tsom, thiab nthuav dav cov kev sim tshuaj ntsuam xyuas txog HO{{ 3}} induction rau lwm yam pathologies. Qhov kev tshawb fawb txaus siab nyob rau hauv kaum xyoo dhau los hauv lwm cov tswv yim, xws li kev tswj hwm ntawm heme degradation cov khoom, cuam tshuam qhov xav tau rau cov kws tshawb fawb kom dhau qhov duality ntawm heme thiab HO-1 cov teebmeem. Kev nce qib ntawm CO, los ntawm kev tswj hwm ntawm CO-tso tawm cov molecules, tau pom tau tias muaj txiaj ntsig zoo hauv AKI thiab hauv kev txhim kho kev hloov pauv tau zoo [333–335].
6. Cov lus xaus
HO-1 muaj lub luag haujlwm tseem ceeb hauv kev khaws ciaraumtiv thaiv kev raug mob, tsis tsuas yog nyob rau hauv heme-mediated pathologies tab sis kuj nyob rau hauv ib tug ntau yam ntawm cov kab mob uas sib txawv rau glomeruli, hlab ntsha, thiab tubules nyob rau hauv ib tug mob los yog ntev. Txawm hais tias qhov txiaj ntsig loj ntawm nws qhov kev xav tau xav tau, qhov muaj txiaj ntsig ntawm HO-1 cov ntaub ntawv hauv vitro thiab hauv vivo sib piv nrog cov kev sim tshuaj me me uas tab tom ua rau niaj hnub no. Qhov no qhia txog qhov xav tau ntawm cov ntaub ntawv hais txog cov kev mob tshwm sim ntawm HO-1 induction, tab sis kuj yog rau cov kev tshawb fawb ntxaws ntxiv txhawm rau txhim kho cov cuab yeej kho mob rau qhov tshwj xeeb induction ntawm HO-1 hauv cov qauv sib txawv / hom cell.
Tus sau kev koom tes:AG, LTR, thiab MF tau koom nrog hauv kev npaj thiab sau qhov kev tshuaj xyuas no. Txhua tus kws sau ntawv tau nyeem thiab pom zoo rau cov ntawv luam tawm ntawm cov ntawv sau.
Nyiaj txiag:Txoj haujlwm no tau txais kev txhawb nqa los ntawm cov nyiaj pab los ntawm Francophone Society of Nephrology, Dialysis thiab Transplantation-ASTELLAS 2020 rau MF thiab Fondation pour la Recherche Médicale rau AG
Kev lees paub:Cov kws sau ntawv ua tsaug rau Mike Howsam rau kev nyeem ntawv Askiv. Kev tsis sib haum xeeb ntawm kev txaus siab: Cov neeg sau ntawv tshaj tawm tsis muaj qhov tsis sib haum xeeb ntawm kev txaus siab.
Cov ntaub ntawv
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