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Part 2: Renovascular Effects Of Inorganic Nitrate Tom Qab Ischemia-reperfusion Ntawm Lub raum

May 16, 2022

Yog xav paub ntxiv. tiv taujtina.xiang@wecistanche.com

3. Cov txiaj ntsig

3.1.Nitrate supplementation ua kom cov cim tsis muaj bioactivity thiab ua rau lub raum tsis ua haujlwm tom qab IR

Qib ntawm nitrate thiab nitrite tau nce ntxiv thiab cGMP tau nce ntxiv hauv cov nas tom qab kev kho nitrate (Fig. 1A-C). Lub raum tsis ua haujlwm, raws li kev hloov pauv hauv BUN thiab GFR, kuj tau txhim kho los ntawm nitrate (Fig.1D thiab E).

Effects of nitrate on nitric oxide bioactivity and kidney function following ischemia-reperfusion of the kidney. Plasma nitrate, nitrite, and cGMP levels (A–C), and BUN and GFR (D–E) following ischemia-reperfusion (IR) in mice treated with placebo or nitrate. Data are shown as mean ± SEM. *, **p < 0.05 and 0.01 vs. Sham group; #, ##p < 0.05 and 0.01 vs. IR group, respectively. n = 6–8/group.

3.2. Nitrate txo qis cov ntshav siab thiab lub raum Ang II qib tom qab IR

Tom qab ob lub lis piam ntawm kev rov ua dua, cov ntshav siab tau nce siab me ntsis hauv pawg IR piv nrog kev tswj hwm tus kheej. Kev kho nrog nitrate tiv thaiv qhov siab ntawm cov ntshav siab (Daim duab 2A-C). Txhawm rau tshawb xyuas qhov txuas rau kev hloov pauv hauv renin-angiotensin system peb ntsuas Ang II qib hauv cov ntshav plasma thiabcov ntaub so ntswg. Peb cov ntaub ntawv qhia tias Ang II hauv cov ntshav ntshav zoo ib yam ntawm cov pab pawg, nce hauv lub raum ischemic, tab sis tsis tau hloov pauv hauv lub raum tsis yog ischemic (Fig. 2D-F). Nitrate tiv thaiv qhov nce ntawm Ang Ⅱ hauv lub raum cov ntaub so ntswg tom qab IR, uas tuaj yeem ua rau nws cuam tshuam rau ntshav siab.

Effects of nitrate on blood pressure and Ang II levels following ischemia-reperfusion of the kidney. Systolic, diastolic and mean arterial pressure (A–C), and plasma and intrarenal levels of Ang II (D–F) following ischemia-reperfusion (IR) in mice treated with placebo or nitrate. Data are shown as mean ± SEM. *p < 0.05 vs. sham group, #p < 0.05 vs IR group, n = 4–8/group.

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3.3. Nitrate ameliorates lub raum histopathological hloov, o, thiab apoptosis tom qab IR

Tom ntej no, peb txheeb xyuas cov kev hloov hauv lub raum histopathological tom qab IR los ntawm kev siv H&E thiab PAS staining. IR pab pawg tau nthuav tawm qhov kev puas tsuaj glomerular ua ke nrog tubular necrosis piv nrog sham-kev tswj hwm (Daim duab 3A-F thiab Table 1).IR nas kho nrog nitrate muaj kev hloov pauv histopathological ntau heev, raws li pom los ntawm kev tsim tawm tsawg dua, necrosis, ectasia rupture. ntawm tubular hauv qab daus membrane, thiab ntau dua tubular regeneration thiab necrotic tubules nyob rau hauv regeneration (Fig. 3A-F thiab Table 1). Ntxiv mus, F4/80 immunostaining pom muaj ntau infiltration ntawm macrophages nyob rau hauv lub raum ischemic tom qab IR, uas yog tiv thaiv los ntawm nitrate kev kho mob (Fig.4A thiab B). TUNEL staining, txhawm rau txheeb xyuas apoptosis, tau nce siab tom qab IR raug mob, uas tau txo qis los ntawm nitrate (Fig.4C thiab D)[6].

Effects of nitrate on renal histopathology following ischemia-reperfusion of the kidney. Photomicrographs of the left renal cortex from sham and ischemia-reperfusion (IR) mice treated with placebo or nitrate (A–F). Normal renal parenchyma, without glomerular changes, preserved urinary space (arrow), tubules without atrophy or dilation, absence of necrosis and inflammatory cells, and preserved tubular basement membrane (arrowhead) (A–B). Left renal parenchyma submitted to IR showing loss of organ architecture, tubular ectasia (*), tubules with cells in necrosis and lumen filled of cellular debris (arrow), rupture of the tubular basement membrane (arrowhead) and interstitial inflammatory cells (C–D). Left renal parenchyma submitted to IR and treatment with nitrate, presenting necrosis and tubular ectasia (*), presence of granular cylinders in the tubular lumen (arrow), regenerating cells and preserved tubular membranes (arrowhead) (E–F). Magnification for all photomicrographs presented is ×400.

Quantification of the histopathological findings (%) – Mean ± SEM.

Effects of nitrate on renal inflammation and apoptosis following ischemia-reperfusion of the kidney. Immunostaining images of macrophage infiltration (F4/80, red) in kidneys following ischemia-reperfusion (IR), counterstained with nuclear marker DAPI (scale bar, 50 μm) (A). Quantification of normalized F4/80 intensity (B). Immunostaining images of TUNEL (red) in kidneys following IR injury (counterstained with nuclear marker DAPI, scale bar, 50 μm) (C). Quantification of normalized TUNEL intensity (D). Data in B and D are shown as mean ± SEM. ***p < 0.001 vs. sham group, ###p < 0.0001 vs IR group, n = 6–8/group. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

3.4 Nitrate txhim kho mitochondria raug mob tom qab lub raum IR los ntawm cov txheej txheem uas rov ua kom rov zoo dua ntawm TFAM protein ntau

Lub raum mitochondrial abnormalities thiab dysfunction, ua ke nrog ntau tshaj ROS ntau lawm, yog koom nyob rau hauv lub pathogenesis ntawm lub raum noj. suav nrog AN [27.28]. Peb cov ntaub ntawv qhia tau hais tias mitochondrial transcription factor A (TFAM).uas yog ib qho tseem ceeb regulator ntawm mitochondrial gene qhia [29], tau txo qis hauv IR raum (Hg.5A-C). Kev kho Nitrate tsis cuam tshuam nrog kev hloov pauv tseem ceeb hauv TFAM hauv IR raum tab sis nce nws cov lus qhia hauv lub raum tsis yog ischemic tom qab IR (Fig 5A-C).

3.5. Kev kho Nitrate attenuates Ang II-induced contractility ntawm interlobar hlab ntsha thiab afferent hlab ntsha tom qab lub raum R

Tom ntej no, peb siv cov txheej txheem myography los ntsuas qhov cuam tshuam ntawm IR ntawm vascular kev ua haujlwm hauv cov hlab ntsha loj ntawm lub raum sab laug tom qab rov ua dua. Kev cog lus rau phenylephrine tsis txawv txav ntawm pawg sim (Fig 6A). Txawm li cas los xij, Ang I-induced contractility tau nce ntxiv hauv IR raum (Hg.6B), uas tau tiv thaiv los ntawm kev kho nitrate. Hauv kev sib cais thiab perfused afferent arterioles (Fig.6C), qhov rhiab heev thiab qhov siab tshaj plaws contractile cov lus teb rau Ang II kuj tau nce hauv IR raum, uas tau tiv thaiv ntau los ntawm kev kho nitrate (1. 6D)

3.6.Fypoxia-Treoxygenation-insured cell apoptosis thiab mi chandndl abnormalities nyob rau hauv glomerular endothelial hlwb yog ameliorated los ntawm nitie

Hauv kev tshawb fawb vascular mechanistic ntxiv. tsom rau kev ua raws li tus qauv hauv vivo IR, peb siv GECs. Hauv kev tshawb fawb ntawm tes no peb siv nitrite es tsis txhob nitrate los hla, thawj kauj ruam hauv nitrate-nitrite-NOpathway uas yuav tsum muaj cov kab mob commensal hauv vivo. Hypoxia ua raws li reoxygenation hauv GECs txo cov cell viability / nce mortality (Fg.7A thiab B).

Qhov no tau cuam tshuam nrog nce qib ntawm cleaved caspase-3, txo mitochondrial complex IⅡ thiab TFAM qhia (Fig.7C-G), thiab mitochondrial ROS ntau lawm, raws li qhia los ntawm MitoSox(Fig. 7H). Tag nrho cov kev txawv txav no cuam tshuam nrog hypoxia thiab reoxygenation tau ameliorated los ntawm kev kho mob ib txhij nrog nitrite.

Peb cov ntaub ntawv hauv vivo tau qhia tias IR-induced vascular raug mob thiab ua haujlwm tsis zoo tau ua ke nrog rau lub raum Ang II thiab rhiab heev (Figs.2E thiab 6B thiab D).Nyob rau hauv lub xub ntiag ntawm Ang I, hypoxia-reoxygenation txo cell viability thiab ntxiv mitochondrial. ROS ntau lawm (Fig S1 thiab Fig.8), uas dua tau txo los ntawm nitrite kho.

Effects of nitrate on vascular function following ischemia-reperfusion of the kidney. Phenylephrine (PE) (A) and Angiotensin II (B) induced contractions of renal interlobar arteries following ischemic-reperfusion (IR). Photomicrograph demonstrating the isolated and micro-perfused afferent arteriolar system (C). Angiotensin II-induced contractions of afferent arterioles from the ischemic kidney following IR (D). Changes in luminal diameters are presented as percent of the control diameter. Data are shown as mean ± SEM. *p < 0.05 IR vs. Sham; #p < 0.05 IR + Nitrate vs. IR. n = 9–16 vessels/group in interlobar arteries. n = 5–6 vessels/group in afferent arterioles.

Effects of nitrite on cell viability and mitochondrial function in GECs following hypoxia-reoxygenation. Cell viabilities and mortalities after hypoxiareoxygenation (A–B). Immunoblotting images (C) and quantification of normalized cleaved caspase-3 and OXPHOS complex II proteins expression (D–E) following hypoxia-reoxygenation. Immunoblotting images (F) and quantification of normalized of TFAM protein expression (G) following hypoxia-reoxygenation injury. Mitochondrial production of reactive oxygen species, indicated by MitoSox, following hypoxia-reoxygenation (H). Data are shown as mean ± SEM. *, **p < 0.05, 0.01 vs Control group respectively; #, ##p < 0.05, 0.01 vs. Vehicle group respectively. A: n = 16–18/group; B: n = 8–10/group; C–G: n = 4–6/group; H n= 10–18/group.


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3.7. Kev tiv thaiv ntawm nitrite tom qab hypoxia-reoxygenation hauv glomerular endothelial hlwb raug tshem tawm los ntawm inhibition ntawm xanthine oxidoreductase.

XOR yog suav tias yog ib qho ntawm cov enzymes tseem ceeb koom nrog hauv kev txo cov nitrite rau TSIS TAU thiab lwm yam bioactive nitrogen oxide hom. Ntawm no peb qhia tau tias, nyob rau hauv lub xub ntiag ntawm kev xaiv XOR inhibitor febuxostat, cov txiaj ntsig zoo ntawm nitrite ntawm cell viability, TFAM qhia, thiab mitochondrial ROS (Fig.9A-D) tom qab hypoxia-reoxygenation ua ke nrog Ang I hauv GECs raug tshem tawm. Cov ntaub ntawv ntawm cell viability nyob rau hauv qhov tsis muaj Ang II nyob rau hauv lub tsheb pab pawg neeg yog qhia nyob rau hauv daim duab S2.

Effects of nitrate on TFAM expression following ischemia-reperfusion of the kidney. Immunoblotting images of TFAM, indicating mitochondrial biogenesis, following ischemia-reperfusion (IR) (A). Quantification of normalized TFAM in the ischemia (B) and non-ischemia (C) kidneys following IR (B–C). Data in B and C are shown as mean ± SEM. *p < 0.05 vs. Sham, ##p < 0.01 IR + Nitrate vs. IR group. n = 4–6/group.

Effects of nitrite in GECs following hypoxia-reoxygenation combined with Ang II. MitoSox levels in glomerular endothelial cells (GECs) following hypoxia-reoxygenation in combination with Ang II. Data are shown as mean ± SEM. **p < 0.05, 0.01 vs. Control group respectively; #, ##p < 0.05, 0.01 vs. Vehicle group respectively. n = 10/group

The favorable effects of nitrite on cell viability and mitochondrial function in GECs following hypoxia-reoxygenation combined with Ang II are blocked by febuxostat. Cell viability (A), immunoblotting images of TFAM and quantification of normalized TFAM (B–C) as well as MitoSox levels (D) following hypoxia-reoxygenation in combination with Ang II, with and without inhibition of xanthine oxidoreductase using febuxostat (FEB). Data are shown as mean ± SEM. *, **p < 0.05, 0.01 vs. Ang II group respectively; #, ##p < 0.05, 0.01 vs. Vehicle group. A: n = 28–30/group; B–C: n = 7–8/group; D: n = 8–14/group.

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4. Kev sib tham

Nyob rau hauv txoj kev tshawb no, peb qhia tau hais tias inorganic nitrate kho tam sim ntawd ua ntejlub raum ischemiatxo qis glomerular thiab tubular puas tsuaj nrog rau lub raum tsis ua haujlwm tom qab 2 lub lis piam ntawm reperfusion. Cov txiaj ntsig zoo ntawm nitrate no cuam tshuam nrog cov tshuaj tiv thaiv kab mob thiab angiotensin II, ua ke nrog kev hloov kho ntawm mitochondrial.oxidative kev nyuaj siabthiab cell viability.

Qhov no yog thawj qhov kev piav qhia ntawm yuav ua li cas boost cov nitrate-nitrite-NO txoj hauv kev ua ntej muaj kev tshwm sim ischemic tuaj yeem tiv thaiv lub raum tiv thaiv kev rov qab ua haujlwm ntawm lub raum thiab endothelial dysfunction thiab raug mob.

NOS-derived TSIS MUAJ tiam yog qhov tseem ceeb rau ntau lub plawv thiablub raum ua haujlwm, suav nrog kev hloov pauv ntawm cov ntshav siab thiab lub raum autoregulation nrog rau tubular electrolyte tuav [30-32]. Txawm li cas los xij, nyob rau hauv tej yam kev mob uas tsis tshua muaj oxygen nro thiab pH tsis tshua muaj, qhov no enzymatic system muaj kev cuam tshuam ua rau tsis muaj deficiency los yog txawm uncoupling ntawm NOS, uas ua rau kom zus tau tej cov reactive oxygen hom [6,30]. Lwm txoj hauv kev nitrate-nitrite-NO yog ywj siab ntawm NOS system thiab tuaj yeem txhawb nqa los ntawm peb cov khoom noj txhua hnub. Qhov tseem ceeb, kev ua tau zoo ntawm nitrate-nitrite-NO txoj hauv kev tau txhim kho zoo heev hauv cov xwm txheej nrog ischemia lossis hypoxia thaum NOS system raug cuam tshuam [9,33]. Kev sim thiab kev tshawb fawb soj ntsuam tau pom tias muaj txiaj ntsig zoo ntawm cov hlab plawv ntawm nitrate supplementation, nrog rau kev txhim kho endothelial kev ua haujlwm thiab ntshav siab txo qis hauv cov neeg tsis muaj zog thiab mob siab [1]. Peb tau pom yav dhau los tias lub raum microvasculature zoo heev teb rau nitrite-mediated vasodilatation [23], tshwj xeeb tshaj yog thaum lub sij hawm acidic thiab tsis tshua muaj oxygen tej yam kev mob mimicking hauv vivo ischemic ib puag ncig [20]. Ua ke, cov kev tshawb pom no qhia tias kev kho nitrate tuaj yeem cuam tshuam nrog kev tiv thaiv lub cev tom qab IR.

Cov kev tshawb fawb yav dhau los uas siv cov kev cuam tshuam nitrite tau tsim cov txiaj ntsig tsis sib haum xeeb txog nws cov nqi kho mob hauv nas qauv ntawm IR raug mob [16,17,34,35]. Triptatara thiab al. qhia tau tias mob raum raum kev tswj hwm ntawm nitrite (30} nmol) tiv thaiv cov nas raum tiv thaiv 60 min ob sab ischemia thiab 6h reperfusion-induced raug mob thiab tsis ua haujlwm hauv vivo, tsawg kawg hauv ib feem, ntawm XOR- dependent TSIS MUAJ ntau lawm [16]. Siv tus nas transgenic mus kom ze, kev tshawb pom los ntawm Milsom li al. qhia tias eNOS yog ib qho tseem ceeb ntawm cov neeg ua si, los ntawm kev pab txo nitrite thaum lub sij hawm IR, yog li kev sib kho tiv thaiv [35]. Hauv kev pom zoo, Cantor thiab cov npoj yaig tau pom tias kev tswj hwm tus mob hnyav ntawm nitrite ({18}}.172 ua raws li 0.057 mg/h/kg) txhim kho lub raum reoxygenation thiab rov ua dua tom qab unilateral ischemia (45 min) thiab 60 min reperfusion hauv nas [ 34] ib. Hauv qhov sib piv, Basireddy thiab al.dev tsis pom muaj kev tiv thaiv los ntawm kev tswj hwm tus mob hnyav ntawm nitrite (0.12-12 nmol/g/kg) hauv cov nas raug rau unilateral nephrectomy tom qab 45 min ntawm ischemia ntawm lub raum ntxiv thiab 24-48 h reperfusion [17]. Cov lus piav qhia ua tau rau qhov tsis sib xws no yuav yog cov kev sim sib txawv (xws li IR qauv, lub sijhawm ntawm IR lub sijhawm), kev siv tshuaj, kev tswj hwm, thiab hom sib txawv. Tam sim no, tsis tshua muaj kev paub txog tus nqi kho mob ntawm kev siv cov tshuaj inorganic nitrate es tsis txhob nitrite. Nitrate tuaj yeem muaj kev nyab xeeb hauv cov koob tshuaj ntau dua li nitrite thiab muaj lub neej ntev dua ib nrab (6 h vs.30 min), uas tso cai rau kev tsim cov nitrite tsis tu ncua, NO, thiab lwm yam bioactive nitrogen oxides nyob rau lub sijhawm ntev dua. Nyob rau hauv cov ntsiab lus no, nitrate tej zaum yuav raug suav hais tias yog ib tug prodrug rau ib tug tas mus li tiam ntawm nitrite.

Hauv kev tshawb nrhiav nas yav dhau los, peb tau pom tias kev noj zaub mov nitrate pretreatment rau 2 lub lis piam tiv thaiv lub raum tiv thaiv IR raug mob los ntawm cov txheej txheem uas koom nrog kev hloov pauv ntawm lub cev tiv thaiv kab mob phenotype thiab cov khoom tiv thaiv oxidative [18]. Hloov chaw ntawm kev ua raws li qhov xwm txheej ntawm kev noj tshuaj nitrate ntev ntev, txoj kev tshawb fawb tam sim no tau sim cov kev cuam tshuam ntawm kev tswj xyuas mob ua ntej muaj kev thuam ntawm ischemic. Txoj hauv kev no yog qhov txaus nyiam los ntawm kev saib xyuas thiab kho mob, vim qhov no tuaj yeem zoo li kev cuam tshuam hnyav ua ntej ischemia hauv tus neeg mob uas muaj kev pheej hmoo ntawm kev tsim AKI. Peb txoj kev tshawb fawb tam sim no tau qhia tias kev kho mob hnyav nitrate ua raws li kev noj haus nitrate ntxiv rau 2 lub lis piam ua rau muaj kev nce qib nitrate, nitrite, thiab cGMP hauv kev ncig. Kev soj ntsuam morphological tau pom tias kev kho nitrate ameliorated IR-induced raug mob piv nrog cov tsis kho IR tswj. Nrog rau txo qis lub raum kev puas tsuaj, kev kho nitrate khaws cia raum ua haujlwm tom qab IR raug mob. Vim tias plasma creatinine feem ntau rov qab mus rau qib qub ib lub lis piam tom qab reperfusion [36,37, peb ntsuas BUN thiab GFR los ntsuas lub raum ua haujlwm tom qab 2 lub lis piam ntawm reperfusion. GFR thiab BUN tsis tau hloov pauv loj tom qab IR piv rau kev tswj hwm sham, uas yuav piav qhia los ntawm contralateral compensating raum. Txawm li cas los xij, peb cov ntaub ntawv qhia tau hais tias ob qho tib si ntawm cov kev ntsuas no tau txhim kho tau zoo los ntawm nitrate piv nrog cov pab pawg IR tsis kho.

Inflammatory tebthiab cell apoptosis yog cov txheej txheem lom neeg tseem ceeb thaum lub sij hawm IR raug mob, uas ua rau kev tshem tawm cov khib nyiab ntawm tes thiab kho cov ntaub so ntswg txaus [18,24]. Txawm li cas los xij, kev mob ntev thiab tsis daws teeb meem tuaj yeem ua rau cov ntaub so ntswg raug mob ntxiv [7,38,39].Lub raum mobRaws li pom los ntawm F4/80 staining ntawm macrophage infiltration, tau txo qis los ntawm nitrate tom qab IR. Qhov no tau pom zoo nrog kev tshawb fawb tsis ntev los no los ntawm Yang et al. [18] and Khambata et al. [40] Tsis tas li ntawd, TUNEL kev soj ntsuam rau apoptosis elucidated tias IR raug mob nce lub cell apoptosis hauv nas ischemic raum, uas yog ib feem tiv thaiv los ntawm kev kho nitrate. Ua ke, cov txiaj ntsig no qhia meej meej tias kev kho nitrate tuaj yeem cuam tshuam lub raum mob thiab cell apoptosis uas tshwm sim tom qab IR.

Cov ntaub ntawv pov thawj qhia tau hais tias kev ua haujlwm tsis zoo ntawm mitochondrial tseem ceeb ua rau muaj kev txhim kho ntawm AKI tom qab IR, thiab cov txheej txheem tshiab uas hloov kho mitochondrial muaj nuj nqi yuav muaj txiaj ntsig kho [41-45]. Piv txwv li, nyob rau hauv lub raum ischemic, mitochondria nyob rau hauv endothelial hlwb hloov pauv tau zoo ob qho tib si functionally thiab morphologically, thiab ua heev reactive thiab ua rau lawv tus kheej thiab kuj nyob ib ncig ntawm mitochondria [44]. Peb tau qhia ua ntej tias kev noj haus nitrate txhim kho mitochondrial efficiency hauv tib neeg [46]. Kev txhawb nqa ntawm nitrate-nitrite-NO txoj hauv kev muaj nyob rau hauv ntau qhov kev tshawb fawb tsis ntev los no tau cuam tshuam nrog cov txiaj ntsig zoo ntawm kev ua haujlwm mitochondrial thaum lub sij hawm metabolic, nrog rau hom 2 mob ntshav qab zib, los ntawm cov txheej txheem uas cuam tshuam rau dampening ntawm oxidative stress [47]. Ntxiv mus, Shiva thiab cov npoj yaig tau pom tias kev kho mob ua ntej thiab mob hnyav nrog cov tshuaj tsis muaj zog nitrite muaj cov teebmeem cytoprotective thiab muaj peev xwm txwv tsis pub mob plawv thiab hepatic reperfusion raug mob los ntawm kev hloov pauv ntawm mitochondria electron thauj saw thiab txo ROS [48]. Hauv peb cov qauv hauv vivo IR, TFAM tau nce hauv lub raum tsis yog ischemic, tab sis tsis hloov pauv hauv lub raum ischemic. Xav tias nitrite rov qab kho TFAM kev qhia hauv vitro tom qab hypoxia-reoxygenation peb xav tias qhov no tuaj yeem cuam tshuam nrog lub sijhawm sib txawv ntawm kev qhia. Hauv cov qauv hauv vivo, kev tshuaj xyuas ntawm TFAMwas tsuas yog ua tom qab 2 lub lis piam thiab nws muaj peev xwm hais tias qhov no yuav txawv ntawm lub sijhawm dhau los tom qab rov ua dua.

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Nce Ang I signaling yog dav paub los txhawb NADPH oxidase thiab mitochondria-derived ROS ntau lawm, ua rau oxidative stress [49-51]. Cao thiab cov npoj yaig tau pom tias qhov reno-cerebral reflex tau qhib lub renin-angiotensin system tom qab IR, uas txhawb nqa oxidative kev nyuaj siab thiab kev loj hlob ntawm lub raum raug mob [52]. Peb tau pom yav dhau los tias kev kho nitrate dampens Ang I-mediated contractility hauv lub raum afferent arterioles thiab kub siab los ntawm cov txheej txheem uas cuam tshuam txog kev txo qis kev mob siab rau thiab ua kom cov oxidative kev nyuaj siab, nrog rau kev txo qis ntawm Ang type 1 receptor [53-55 }]. Raws li qhov kev tshawb pom yav dhau los, peb cov ntaub ntawv qhia tau hais tias kev kho nitrate txo cov ntshav siab uas cuam tshuam nrog qis Ang II theem hauv ob lub raum tom qab IR thiab dampened Ang IⅡ-kev kho mob contractility nyob rau hauv ob qho tib si interlobar hlab ntsha thiab afferent arterioles.

Txij li thaum endothelial cell abnormalities tom qab IRis yog ze rau kev raug mob rau lub raum thiab lub raum tsis ua hauj lwm, peb tom ntej no siv glomerular endothelial hlwb (GECs) rau kev tshawb fawb mechanistic. Ib qho qauv hauv vitro hypoxia-reoxygenation, nrog thiab tsis muaj kev kho nitrate ib txhij, tau siv los ua cov qauv hauv vivo IR scenario. Peb cov txiaj ntsig hauv vitro qhia tau tias hypoxia-reoxygenation nce cell tuag, mitochondrial ROS ntau lawm, thiab cleaved caspase-3, txo qis cell viability thiab protein qhia ntawm OXPHOS complex I thiab TFAM. Tag nrho cov kev hloov pauv txawv txav no tau ua kom zoo dua los ntawm nitrite.

Raws li peb cov ntaub ntawv hauv vivo tau pom tias Ang I qib tau nce hauv ob lub raum tom qab IR, peb kuj tau kawm txog cov txiaj ntsig ntawm nitrite kho hauv GECs tom qab hypoxia-reoxygenation nyob rau hauv lub xub ntiag ntawm Ang. Peb cov ntaub ntawv qhia tau hais tias hypoxia-reoxygenation nyob rau hauv ua ke nrog Ang I ntxiv txo cov cell viability thiab nce mitochondrial ROS ntau lawm, uas dua tau tiv thaiv los ntawm ib txhij nitrate kev kho mob.

Thaum lub sij hawm normoxia thiab ib txwm pH, NOS-derived NO yog oxidized rau nitrite thiab nitrate, tab sis thaum lub sij hawm hypoxia thiab acidic tej yam kev mob, nitrite yuav txo tau rov qab mus rau NO los ntawm cov nitrite reductase kev txiav txim ntawm XOR. Co-incubation nrog cov xaiv XOR inhibitor febuxostat tshem tawm cov kev tiv thaiv ntawm nitrite tom qab hypoxia-reoxygenation hauv GECs. Cov ntaub ntawv no qhia tias XOR catalyzes nitrite txo rau NO, uas nyob rau hauv lem mediates tiv thaiv cov hlwb los ntawm hypoxia-reoxygenation-induced raug mob.

Qee qhov kev txwv ntawm txoj kev tshawb fawb tam sim no suav nrog cov pab pawg nrog kev kho nitrate ib leeg hauv cov tsiaj sham-ua haujlwm tsis suav nrog. Lub ntsiab yog vim li cas rau qhov no yog tias yav dhau los cov kev tshawb fawb nyob rau hauv ib txwm nas thiab nas tsis tau pom muaj kev cuam tshuam loj, siv cov tshuaj nitrate zoo sib xws, ntawm cov ntshav siab, lub raum ua haujlwm, lossis vascular reactivity. Lwm qhov kev txwv yog tias tag nrho hauv vivo tus cwj pwm tau ua tsuas yog tom qab ob lub lis piam ntawm reperfusion. Lub sijhawm ntxiv cov ntsiab lus tuaj yeem ua rau muaj kev nkag siab ntau dua ntawm kev siv tshuab.

Hauv kev xaus, kev kho mob hnyav nrog inorganic nitrate ua ntej lub raum ischemia tshwm sim, ua raws li kev noj zaub mov noj nitrate thaum lub sijhawm ob lub lis piam ntawm kev rov ua dua, tiv thaiv lub raum tsis ua haujlwm thiab raug mob los ntawm cov txheej txheem uas cuam tshuam txog kev txo qis ntawm infiltrating inflammatory cells thiab angiotensin I qib hauv ischemic. lub raum nrog rau kev hloov pauv ntawm mitochondrial kev ua haujlwm. Cov kev sim tshuaj ntsuam xyuas yav tom ntej yuav qhia tau meej yog tias kev cuam tshuam nrog inorganic nitrate tuaj yeem muab cov txiaj ntsig zoo rau cov neeg mob uas muaj kev pheej hmoo siab ntawm kev mob raum IR.



Koj Tseem Yuav Zoo Li