Kev kho mob raum: Nitric Oxide (NO) Nws pib tswj lub raum ua haujlwm li cas?

Yog xav paub ntxiv:ali.ma@wecistanche.com

Ntu Ⅰ: Nitric oxide signaling nyob rau hauv lub raum tswj thiab cardiometabolic noj qab haus huv

Mattias Carlström

Feem ntau ntawm cov kab mob plawv, nrog rau cov ntshav siab, thiab cov kab mob metabolic xws li hom 2 mob ntshav qab zib mellitus (T2DM), yog nce thoob ntiaj teb. Cov kab mob no yog sib txuas nrog kev txhim kho thiab kev loj hlob ntawmmob raum, uas ua rau kom cov neeg mob morbidity thiab tuag. Qhov tshwm sim ntawm kev lag luam kev lag luam hauv zej zog yog qhov loj heev thiab kev nkag siab ntxiv ntawm cov txheej txheem pathophysiological yog qhov xav tau sai sai los pab txhim kho kev tiv thaiv tshiab thiab kho cov tswv yim noj zaub mov thiab tshuaj. Covraum, mob plawv thiab metabolic phenotypes (uas yog,mob raum, kab mob plawv, thiab T2DM) muaj kev sib cuam tshuam, qhia tias qhov triad ntawm cov teeb meem no qhia txog cov txheej txheem pathological. Qhov laj thawj tiag tiag ntawm cov teeb meem no, kev cuam tshuam ntawm cov kab mob hauv nruab nrog cev, thiab cov txheej txheem pathophysiological nyuaj uas cuam tshuam qhov pib, kev saib xyuas, thiab kev loj hlob ntawm tus kab mob yog qhov nyuaj thiab tsis nkag siab tag nrho.

Nyem rau cistanche hmoov cov txiaj ntsig kev noj qab haus huv thiab Cistanche rau mob raum

Muaj peev xwm mechanisms uas yuav pab tau rau txoj kev loj hlob ntawmmob raum, kab mob plawv, thiab T2DM suav nrog hyperglycemia, hloov pauv lipid metabolism, qis-qib o, overactivity ntawm renin-angiotensin-aldosterone system (RAAS), nce siab sympathetic paj hlwb, thiab hloov micro-biota 3-6. Tsis tas li ntawd, ntau qhov kev tshawb fawb tau qhia tias muaj txiaj ntsig zoo ntawm kev nce qib ntawm NADPH oxidase-derived thiab mitochondria-derived reactive oxygen hom (ROS) thiab oxidative kev nyuaj siab ua ke nrog txo qis.nitric oxide(NO) bioactivity thiab endothelial dysfunction 7-1. TSIS MUAJ (nitric oxide) yog ib lub sij hawm luv luv diatomic signaling molecule uas exerts ntau yam teebmeem rauraum, mob plawv thiab metabolic ua haujlwm, suav nrog kev hloov pauv ntawmlub raumautoregulation, tubular kua thiab electrolyte thauj, vascular tone, ntshav siab, platelet aggregation, tiv thaiv cell activation, insulin-glucose homeostasis, thiab mitochondrial muaj nuj nqi. Classical saib yog li ntawdnitric oxidesynthase (NOS) systems yog qhov tseem ceeb ntawm endogenous NO (nitric oxide)tsim. Txawm li cas los xij, muaj lwm txoj hauv kev uas muaj cov khoom siv oxidation inert ntawm NO (nitric oxide), uas yog, inorganic nitrate thiab nitrite, undergo serial txo kom tsim NO thiab lwm yam uas muaj feem xyuam nrog bioactive nitrogen oxide hom-1.

Lub luag haujlwm tseem ceeb ntawm NO (nitric oxide)nyob rau hauv txoj cai ntawmraum, mob plawv thiab metabolic kev ua haujlwm hauv kev noj qab haus huv thiab kab mob tau ua rau muaj kev txaus siab ntau hauv kev txheeb xyuas cov txheej txheem rau kev kho mob NO. (nitric oxide)bioactivity. Hauv Kev Ntsuam Xyuas no, kuv tham txog lub luag haujlwm ntawm lub cev ntawm NO (nitric oxide), qhov cuam tshuam ncaj qha thiab tsis ncaj los ntawm qhov no molecule influencesraummuaj nuj nqi, thiab nws koom nrog cov teeb meem cardiometabolic. Kuv kuj tseem hais txog cov txheej txheem tshiab los kho NO (nitric oxide)homeostasis thaum lub sij hawm NOS deficiency nrog rau kev tsom mus rau lwm txoj nitrate-nitrite-NO (nitric oxide)txoj hauv kev, uas tuaj yeem txhawb nqa los ntawm kev noj zaub mov kom tsawg, tshwj xeeb yog noj zaub ntsuab.

Tswj thiab txhim kho lub raum ua haujlwm: nitric oxide (NO) thiab cistanche

Classical NO (nitric oxide)synthase systems

TSIS MUAJ (nitric oxide)yog endogenously tsim los ntawm ntau lub hlwb thoob plaws lub cev ntawm peb lub NOS sib txawv (FIG.1)1-1. Neuronal NOS (nNOS; tseem hu ua NOS1) thiab endothelial NOS (eNOS; tseem hu ua NOS3) yog constitutively qhia, whereas inducible NOS (iNOS; tseem hu ua NOS2) yog feem ntau txuam nrog inflammatory mob6,17.L-Arginine, molecular Oxygen, NADPH thiab tetrahydrobiopterin (BH) yog qhov tseem ceeb sib npaug ntawm cov substrates lossis co-factors uas ua rau muaj qhov sib npaug ntawm NO. (nitric oxide)thiab L-citrulline18,19. Hauv endothelium, eNOS-derived NO (nitric oxide)muaj lub luag haujlwm tseem ceeb hauv kev tswj cov ntshav khiav thiab kev saib xyuas ntawm endothelial kev ncaj ncees. Kev ua haujlwm ntawm eNOS thiab nNOS yog tswj hwm los ntawm cov calcium intracellular, uas ua kom muaj zog calmodulin. Nyob rau hauv lem, calmodulin khi thiab nce NOS enzyme kev ua si. Cov txheej txheem no ua rau NO (nitric oxide)-mediated activation ntawm soluble guanylate cyclase (sGC) thiab nce kev tsim ntawm cyclic GMP (cGMP), uas activates cGMP-dependent protein kinases. Qhov no NO-sGC-cGMP kev taw qhia txoj kev kho kom haum ntau ntawm cov teebmeem ntawm NO (nitric oxide)bioactivity ntawm cov hlab plawv, B, thiab metabolic functions20. Txawm li cas los xij, lwm hom bioactive nitrogen oxide tsim los ntawm cov tshuaj tiv thaiv NO (nitric oxide)tuaj yeem ua rau lwm txoj hauv kev tseem ceeb ntawm lub cev muaj zog-ling txoj hauv kev, suav nrog kev hloov pauv tom qab kev hloov pauv ntawm cov proteins, ywj pheej ntawm cGMP signaling21-23 (Daim duab 1). Cov bioactive nitrogen oxide hom muaj xws li mobile nitrosyl-heme (heme-NO (nitric oxide)2, dinitrosyliron complexes²5, S-nitrosothiols,nitrogen dioxide(NO) 7, dinitrogen trioxide, nitrosopersulfides8, nitroxyl, thiab peroxynitrite3. Oxidation ntawm NO (nitric oxide)los tsim kom ruaj khov anions nitrite thiab nitrate kuj muab ntau nyob deb NO (nitric oxide)- zoo li bioactivity.

NOS kuj tau hloov kho los ntawm kev hloov kho tom qab kev txhais lus nyuaj, suav nrog acylation, nitrosylation, phosphorylation, acetylation, glycosylation thiab glutathionylation ntawm ntau qhov chaw, nrog rau kev sib cuam tshuam ntawm cov protein-protein thiab kev tswj hwm ntawm subcellular localization, uas tuaj yeem nce lossis txo lawv cov kev ua haujlwm enzymatic. {2}}. Kev hloov pauv loj hauv nNOS thiab eNOS kev ua haujlwm hauv vasculature thiabraumFeem ntau yog hloov kho los ntawm cov txheej txheem kev txhais lus tom qab, qhov kev hloov pauv ntev hauv NOS synthesis raug tswj los ntawm kev hloov pauv eNOS lossis nNOS cov ntawv sau thiab txhais lus 183435. Kev ua kom ntawm iNOS yog txuam nrog cov txheej txheem inflammatory thiab ua rau cov qib siab dua ntawm NO (nitric oxide)dua li cov uas tau tsim los ntawm kev ua haujlwm ntawm lwm cov NOS isoforms. Qhov tshwm sim mob hnyav nce hauv NO (nitric oxide)muaj txiaj ntsig antimicrobial los tiv thaiv kab mob, kab mob, thiab fungi. Txawm li cas los xij, induction ntawm iNOS kuj tseem cuam tshuam nrog kev mob qis qis hauv cov hlab plawv, metabolic, thiabraum tsis meej pem*.

Cov txheej txheem NOS feem ntau xav tias yog lub hauv paus tseem ceeb ntawm endogenous NO (nitric oxide)ntau lawm thiab teeb liab nyob rau hauv ib txwm muaj, noj qab haus huv tej yam kev mob, tab sis feem ntau dysfunctional nyob rau hauv pathological tej yam kev mob nrog rau cov hlab plawv thiab cov hlab ntsha.mob ntev raumkab mob(CKD) 7,8. Qhov kev ua haujlwm tsis zoo no cuam tshuam nrog txo NO (nitric oxide)bioactivity. Cov txheej txheem uas ua rau txo qis NO (nitric oxide)Kev tsim thiab kev cuam tshuam cov teeb liab yog multifactorial thiab suav nrog txo NOS kev qhia, txwv tsis pub muaj substrate, uncoupling ntawm NOS, nce qib ntawm endogenous NOS inhibitors xws li asymmetric dimethylarginine thiab cuam tshuam cov teeb liab hauv xeev ntawm oxidative kev nyuaj siab vim ncaj qha scavenging los ntawm ROS los yog oxidation ntawm heme pawg. nyob rau hauv sGC (Fe² rau Fe ntxiv), uas ua rau nws insensitive rau ua kom los ntawm NO9,9.

Daim duab 1|Txoj hauv kev NoS thiab muaj peev xwm cuam tshuam ntawm Tsis muaj rau ntawm lub plawv, lub raum thiab cov metabolism hauv lub cev.

Nitric oxide(NO) yog endogenously tsim los ntawm peb qhov sib txawv nitric oxide synthase (NOS) isoforms: neuronal NOS (nNOS), inducible (iNOS) thiab endothelial NOS (eNOS). Cov kev ua ntawm cov enzymes no yog cov pa oxygen nyob thiab yuav tsum tau l-arginine thiab ntau co-factors (calmodulin, nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin (BH4), flavin adenine dinucleotide (FAD) thiab flavin mononucleotide (FMN). TSIS MUAJ (nitric oxide)khi rau qhov txo qis heme site (Fe2 ntxiv) ntawm soluble guanylyl cyclase (sGC), uas ua kom cov enzyme no, ua rau kev tsim ntawm tus xa xov thib ob cyclic GMP (cGMP) los ntawm GTP. TSIS MUAJ (nitric oxide)yog ib tug luv luv molecule uas yog oxidized nyob rau hauv cov ntshav thiab cov ntaub so ntswg tsim nitrite (NO3−), nitrate (NO2−) thiab lwm yam bioactive nitrogen hom. TSIS MUAJ (nitric oxide)bioactivity tau cuam tshuam nrog ntau cov txiaj ntsig zoo hauv cov hlab plawv,lub raumthiab cov kab mob metabolic, feem ntau yog los ntawm cGMP-dependent mechanisms, txawm hais tias cGMP-kev ywj pheej mechanisms kuj tau tshaj tawm. Cov txheej txheem no yog multifactorial thiab koom nrog kev hloov pauv ntawm cov protein ua haujlwm thiab lub cev tiv thaiv kab mob, txo qis hauv angiotensin II (Ang II) signaling, oxidative kev nyuaj siab, thiab kev ua siab zoo paj hlwb, thiab kev hloov pauv ntawm mitochondrial muaj nuj nqi. GFR, glomerular pom tus nqi.

Lub raum qhia ntawm NOS isoforms

Kev nthuav qhia ntawm tag nrho peb NOSisoforms thiab sGC tau tshaj tawm nyob rau hauvraum, txawm hais tias qee qhov tsis sib xws muaj nyob rau hauv cov lus qhia theem ntawm nephron thaum sib piv cov ntaub ntawv los ntawm tib neeg thiab tsiaj kev tshawb fawb. Ntxiv mus, splice variants ntawm nNOS thiab iNOS40,41 tuaj yeem cuam tshuam lawv cov haujlwm thiab kev ua haujlwm. Hauv macula densa, splice variants (a, , thiab y isoforms) tau tshaj tawm tias muaj kev cuam tshuam loj heev rau kev ua haujlwm ntawm nNOS, yog li hloov kho renin secretion thiab autoregulatory mechanisms.

Kev nthuav qhia ntawm nNOS hauv macula densa thiab eNOS hauvraumvasculature tau sau tseg tsis tu ncua; qee qhov tab sis tsis yog txhua qhov kev tshawb fawb kuj tau tshaj tawm eNOS qhia hauv tubular epithelial hlwb. Nyob rau hauv ib txwm muaj, noj qab nyob zoo tib neegraumCov ntaub so ntswg kuaj, nNOS protein thiab mRNA qhia tau pom nyob rau hauv feem ntau ntawm cov nephron, nrog rau cov macula densa, proximal tubule, tuab ascending limb (TAL) ntawm lub voj ntawm Henle, distal tubule, thiab sau duct. eNOS tsuas yog qhia nyob rau hauv endothelium thiab iNOS tsis tau kuaj pom nyob rau hauv ib qho ntawm cov kev sim. Qhov kev qhia ntawm NOS, uas tau lees paub tias siv cov kev tshawb fawb enzyme, feem ntau pom tias muaj siab dua hauv cortex dua li hauv medulla. Cov ntaub ntawv los ntawm Human Protein Atlas txhawb cov kev tshawb pom no, qhia tias nNOS tau qhia hauv cortical tubules tab sis tsis nyob rau hauv glomeruli thiab eNOS tau qhia hauv glomeruli tab sis tsis nyob hauv tubules. Ntxiv mus, iNOS tau qhia nyob rau theem qis hauv tubules tab sis tsis nyob hauv glomeruli. Seb puas los yog tsis tsim nyog iNOS kev qhia muaj lub luag haujlwm ua haujlwm hauv kev noj qab haus huvraumyog qhov tsis sib haum xeeb, tab sis lub cev muaj txiaj ntsig ntawm cov pov thawj pom tau tias muaj kev qhia ntau ntxiv hauv iNOS thiab kev ua haujlwm thaum lub sijhawm pathological cuam tshuam nrog kev mob, xws li ischemia-reperfusion raug mob (IRI)4, ureteral obstruction4, lipopolysaccharide-induced endotoxemia lossis sepsis, thiab CKD47,48.

Nitrate-nitrite-NO (nitric oxide)txoj kev

Redox cov tshuaj tiv thaiv nrog lwm cov radicals thiab cov hlau hloov pauv, xws li cov hauv cov proteins heme, metabolize sai NO. (nitric oxide)(t~0.05-1 s) los tsim lwm hom nitrogen oxide ruaj khov, suav nrog nitrite thiab nitrate051. Raws li cov anions no mas excreted los ntawm covlub raum, cov txiaj ntsig ntawm lawv qhov tso zis tag nrho (lub npe NOx) thaum lub sijhawm 24-h feem ntau tau siv los kwv yees tag nrho lub cev NOS kev ua haujlwm. Txawm li cas los xij, circulating nitrate thiab nitrite kuj tuaj yeem hloov mus rau bioactive NO (nitric oxide)hom ntawm endogenous serial txo, uas yog, nitrate-nitrite-NO (nitric oxide)txoj kev 1-13 (Fig.2).

Ntxiv mus, kev noj zaub mov muaj txiaj ntsig zoo rau lub cev pas dej ntawm nitrate thiab nitrite -5. Noj nitrate uas nkag mus rau hauv cov hlab ntsha yog nquag coj los ntawm cov qog qaub ncaug thiab tom qab ntawd cov ntsiab lus thiab tawm hauv cov qaub ncaug (cov txheej txheem no hu ua enterosalivary ncig ntawm nitrate) 45. Cov ntaub ntawv pov thawj qhia tau hais tias cov kab mob commensal nyob rau hauv lub qhov ncauj kab noj hniav muaj lub luag haujlwm tseem ceeb hauv thawj kauj ruam ntawm kev txo cov nitrate rau nitrite34.Nyob rau hauv cov kua qaub gastric milieu, nqos nitrite yog sai protonated thiab tsis-enzymatically cov ntaub ntawv NO. (nitric oxide)thiab lwm hom nitrogen nrog nitrosating thiab nitrating zog 7. Txawm li cas los xij, feem ntau ntawm cov nqos nitrate / nitrite yog sai thiab ua tau zoo reabsorbed nyob rau hauv lub plab hnyuv system thiab nkag mus rau hauv txoj kev uas muaj ntau yam uas tsis yog-enzymatic (deoxyhemoglobin, oxymyoglobin) thiab enzymatic systems (xanthine oxidoreductase (XOR), mitochondrial complexes, thiab daim siab cylindrical complexes). txo nitrite rau NO (nitric oxide) 859. Nitrate thiab nitrite tuaj yeem teeb liab tsis tau tsuas yog los ntawm classical NO-sGC-cGMP txoj hauv kev tab sis kuj los ntawm nitration thiab nitrous (yl) kev ua haujlwm mechanisms uas tau kho los ntawm lwm hom bioactive nitrogen ntawm nws tus kheej ntawm sGC-cGMP signaling (FIG.3) . Cov kab mob bioactive nitrogen tuaj yeem cuam tshuam ntau yam ntawm tes ua haujlwm los ntawm kev hloov pauv ntawm cov proteins, lipids, nucleosides, hlau, thiab kev sib hloov / transnitrosylation.

In contrast to NOS-dependent NO (nitric oxide)tiam, nitrate-nitrite-NO (nitric oxide)Txoj kev yog oxygen-ywj siab thiab potentiates thaum lub sij hawm cov xwm txheej tsis tshua muaj oxygen tension (uas yog, hypoxia thiab ischemia) thiab pH- tsawg. Cov nyhuv no tuaj yeem piav qhia los ntawm kev ua kom zoo dua uas tsis yog-enzymatic txo ntawm nitrite los ntawm protonation nyob rau hauv ntau acidic tej yam kev mob. Thaum lub sij hawm hypoxic mob, txhim kho kev ua ub no ntawm enzymes xws li XOR thiab tsim deoxyhemoglobin kuj ua rau kom muaj zog bioactivity ntawm TSIS. (nitric oxide)los ntawm kev pab kom txo tau nitrite, thiab tej zaum kuj nitrate, mus rau NO (nitric oxide) 34. Txawm li cas los xij, kev taw qhia los ntawm nitrate-thiab nitrite-derived bioactive hom kuj tshwm sim thaum lub sij hawm normoxia hauv tib neeg, raws li muaj pov thawj los ntawm kev txo cov ntshav siab thiab vasodilatation tom qab kho nrog nitrate thiab nitrite, raws li (sib tham ntxiv hauv qab no).

Daim duab 2|Kev tsim ntawm bioactive NO (nitric oxide)nyob rau hauv cov tsiaj. Nitric oxide(NO) yog classical saib kom tsim los ntawm NO synthase (NOS) txoj kev tab sis kuj tuaj yeem tsim los ntawm cov txheej txheem sib txawv, cov nitrate (NO3−)–nitrite (NO2−)–NO txoj hauv kev. Thaum lub sij hawm ib txwm muaj oxygen nruj thiab pH, TSIS MUAJ thiab lwm yam bioactive nitrogen hom yog oxidized los tsim inorganic nitrite thiab nitrate nyob rau hauv cov ntshav thiab cov ntaub so ntswg. Circulating NO3- thiab NO2- tuaj yeem txo qis rov qab mus rau NO thiab lwm yam bioactive nitrogen hom ntawm non-enzymatic thiab enzymatic systems. Txoj kev hloov pauv no ntawm TSIS TAU yog qhov tseem ceeb tshwj xeeb thaum lub sij hawm tsis tshua muaj oxygen (uas yog, ischemia thiab hypoxia) thiab acidic mob. Ntxiv rau NOS-derived NO3-, uas yog tsim tom qab oxidation ntawm NO, kev noj zaub mov tsis muaj zog nitrate yog ib qho tseem ceeb rau lub pas dej ntawm cov anion hauv lub cev. Hauv particular, cov nplooj ntsuab ntsuab thiab beetroot muaj cov qib siab ntawm inorganic nitrate. Cov kab mob hauv qhov ncauj yog qhov tseem ceeb rau kev txo qis ntawm NO3- rau NO2-, qhov hloov pauv ntawm NO2- rau NO tshwm sim hauv acidic milieu ntawm lub plab thiab cov hlab ntsha vim yog cov tsis-enzymatic thiab enzymatic systems (piv txwv li, deoxyhemoglobin (deoxyhemoglobin). -Hb), deoxymyoglobin (deoxy-Mb), xanthine oxidoreductase (XOR) thiab mitochondrial complexes). eNOS, epithelial NOS; iNOS, inducible NOD; NOS, NOS NOS.

Daim duab 3|cgMp-kev ywj pheej signaling ntawm bioactive nitrogen hom. Covnitric oxidesynthase (NOS) systems thiab serial txo nitrate (NO3−) thiab nitrite (NO2-ua rau tsim nitric oxide (NO•) thiab lwm yam bioactive nitrogen hom. (cGMP) taw qhia thiab hloov kho cov proteins, lipids, nucleosides thiab hlau ntxiv rau induce transliteration, uas tuaj yeem hloov cov noob qhia, receptor signaling, enzyme kev ua thiab mitochondrial muaj nuj nqi thiab elicit antioxidant, anti-inflammatory, antifibrotic thiab inotropic teebmeem. ; eNOS, epithelial NOS; heme-NO, nitrosyl-heme; iNOS, inducible NOS; N2O3, dinitrogen trioxide; nNOS, neuronal NOS; NO2•, nitrogen dioxide; ONOO-, peroxynitrite; SNO, S-nitrosothiols.

Lub luag haujlwm ntawm NO (nitric oxide)nyob rau hauv lub raum autoregulation

Lub raumautoregulatory mechanisms ua haujlwm ua ke los tswj cov ntshav ntws tsis tu ncua thiab glomerular filtration rate (GFR) txawm tias muaj kev hloov pauv hauvlub raumperfusion siab tshaj qhov dav (80-180mmHg). Cov txheej txheem no tseem ceeb heev los tiv thaiv barotrauma5.

Myogenicresponse thiab tubuloglomerular tawm tswv yim Autoregulation feem ntau kho los ntawm cov lus teb myogenic, macula densa-derived tubuloglomerular tawm tswv yim (TGF), thiab lawv cov kev sib cuam tshuam5. Ob qho tib si mechanisms regu-late pre-glomerular tone feem ntau los ntawm kev hloov pauv ntawm afferent arteriolar txoj kab uas hla, uas yog qhov chaw effector. Ntxiv mus, lub suab thiab contractility ntawm afferent arterioles yog modulated los ntawm cov concentration thiab kev sib cuam tshuam ntawm ob peb endogenous vasoactive tshuaj, nrog rau NO. (nitric oxide), angiotensin II (Ang II), thiab adenosine, nyob rau hauv lub juxtaglomerular apparatus, raws li zoo raws li kev ua ntawm lub sympathetic paj hlwb -7.

Cov txheej txheem uas pab txhawb rau myogenic thiab TGF cov lus teb thiab lawv cov kev sib cuam tshuam hauv kev noj qab haus huv, kub siab,mob raum, thiab ntshav qab zib, koom nrog kev hloov pauv hauv NO (nitric oxide)thiab ROS signaling. Lub myogenic TGF nrog rau lawv cov kev sib cuam tshuam yog mod- teb thiab Tiulated los ntawm NOS-derived NO (nitric oxide). Cov teebmeem ntawm cov tsis xaiv thiab xaiv NOS inhibitors raulub raumautoregulation, kho los ntawm myogenic thiab TGF cov lus teb, tau raug soj ntsuam hauv ntau yam kev sim ua qauv. Hauv naslub raumhauv vivo, thawj zaug nce hauvlub raumvascular kuj nyob rau hauv thawj 5s tom qab ib tug nce nyob rau hauv perfusion siab, uas sib haum mus rau lub myogenic teb, yog heev exaggerated nyob rau hauv qhov chaw ntawm tsis xaiv NOS inhibition48. Txawm li cas los xij, tsis muaj qhov cuam tshuam loj ntawm NOS inhibition tau pom nyob rau theem tom qab (5-25 s) tom qab nce siab perfusion, sib xws rau TGF cov lus teb. Lwm txoj kev tshawb fawb hauv nas hauv vivo tau pom tias NOS inhibition txo cov hlab ntsha thiab ua rau cov lus teb myogenic, raws li pom los ntawm kev txo qis hauv vascular admittance nce (hauv cheeb tsam sib haum rau cov lus teb myogenic) thiab kev nce siab ntawm kev nkag mus rau zaus. Tsis tas li ntawd, kev xaiv inhibition ntawm nNOS hauv macula densa tsis ua rau vasoconstriction ntau heev tab sis tau ua kom muaj zog cov lus teb myogenic, qhia txog kev sib cuam tshuam ntawm ob cov lus teb autoregulatory. Hauv nas hydronephroticraumKev npaj, uas tsis muaj kev ua haujlwm TGE, NOS inhibition tsis muaj kev cuam tshuam rau kev hloov pauv hauv cov kab mob afferent arteriole (uas yog, cov lus teb myogenic). Ex vivo thwmsim siv cais thiab perfused ib leeg arterioles, pom tias tsis muaj qhov sib txawv ntawm cov lus teb arteriolar tom qab nce perfusion siab (uas yog, cov lus teb myogenic) ntawm cov hlab ntsha los ntawm eNOS knockout nas thiab cov tsiaj qus-hom tswj *. Lwm txoj kev tshawb fawb siv hauv vitro ntshav-perfused juxtamedullary nephron npaj tau pom tias inhibition ntawm nNOS nce arteriolar autoregulatory teb rau nce perfusion siab7.

Cov kev tshawb pom no qhia meej txog lub luag haujlwm tseem ceeb ntawm NOS-derived NO (nitric oxide)hauvlub raumautoregulation. Kev koom tes ntawm eNOS piv rau nNOS hauv kev hloov pauv cov lus teb myogenic yog sib cav vim muaj qhov sib txawv ntawm qhov kev tshawb pom nyob ntawm qhov chaw sim. Txawm li cas los xij, cov ntaub ntawv muaj txhawb nqa lub luag haujlwm tseem ceeb ntawm macula densa nNOS-derived NO (nitric oxide)nyob rau hauv dampening ceev thiab lub zog ntawm myogenic teb 5. Qhov tseeb cellular txheej xwm uas NO (nitric oxide)attenuates afferent arteriolar vascular du nqaij cell contraction thaum lub sij hawm myogenic cov lus teb yog incompletely to taub 5. Tsis yog, cGMP lossis nws lub hom phiaj protein kinase G (PKG; tseem hu ua PRKG1) thiab cyclic adenosine monophosphate los yog protein kinase A tuaj yeem ua rau Ca2² signaling lossis rhiab heev, thiab yog li ntawd nruab nrab arteriolar tones73, ntawm ntau lub tshuab, piv txwv li, los ntawm inhibiting voltage-ua haujlwm calcium channels los yog transient receptor tej zaum yuav cation channels, los ntawm activating loj-conductance calcium-activated poov tshuaj raws, los ntawm suppressing ADP-ribosyl cyclase kev ua si thiab yog li ua rau txo ryanodine receptor-mediated Ca2 * mobilization los yog los ntawm NO-mediated kev cuam tshuam thiab / los yog scavenging ntawm ROS.

TGF cov txheej txheem ua haujlwm loj heev los ntawm kev nce tubular sodium-chloride load ntawm macula densa, uas ua rau cov haujlwm ntawm apical Na'-Kt-2Cl-cotransporter (NKCC2; tseem hu ua SLC12A1) thiab lwm yam tubular transporters , ua rau ATP tiam thiab / lossis cov metabolism thiab tsim cov adenosine. Qhov tshwm sim ntawm adenosine A, (REFS3,74) thiab / lossis purinergic P, (REF7) receptors ntawm cov leeg nqaij leeg uas nyob ib sab txhawb cov calcium uas nyob ntawm qhov taw qhia thiab kev cog lus ntawm afferent arteriole76 (FIG.4). Cov ntaub ntawv pov thawj muaj qhia tias nNOS tau nthuav tawm ntau hauv macula densa hlwb thiab muaj lub luag haujlwm ua haujlwm hauv kev tswj hwm ntawm TGF thiab tsawg kawg yog cov kev cai luv luv ntawm ntim homeostasis. Thaum ntxov hauv vivo, cov kev tshawb fawb micropuncture hauv cov nas pom tau hais tias cov tshuaj hauv zos inhibition ntawm NOSin macula densa tau cuam tshuam nrog txo qis glomerular capillary siab, qhia tau hais tias muaj cov lus teb TGF sensitized thiab exaggerated. Qhov kev txo qis hauv glomerular capillary siab tom qab NOS inhibition raug tshem tawm los ntawm kev tswj hwm tubular ib txhij ntawm NKCC2 blocker furosemide. Cov kev tshawb fawb tom qab uas siv cov kev sib txawv (piv txwv li, ex vivo ob chav microperfusion JGA npaj thiab transgenic nNOS knockout nas0) muab pov thawj ntxiv tias nNOS dampens TGF cov lus teb. Kev cuam tshuam nNOS muaj nuj nqi hauv macula densa tau cuam tshuam nrog kev kub siab,raumkab mobthiab ntshav qab zib 81. Cov kev tshawb fawb thaum ntxov tau pom tias cov nas mob ntshav siab tsis tu ncua thiab Milan cov kab mob ntshav siab ntawm cov nas muaj qhov txawv txav nNOS ua haujlwm thiab qhov cuam tshuam ntev ntawm nNOS nce TGF rhiab heev, txo GFR thiab ntsev thiab dej tawm thiab tom qab ntawd ua rau kub siab. Txawm hais tias nNOS tau qhia hauv tib neegraum3, nws lub luag haujlwm ua haujlwm thaum lub sijhawmlub raumautoregulation nyob rau hauv kev noj qab haus huv thiab kab mob tseem yog ib tug loj unexplored teb.

Zuag qhia tag nrho, physiological qhov tseem ceeb ntawm kev sib cuam tshuam ntawm vascular thiab tubular mechanisms uas kho autoregulation hauv lub cev.raumtseem elusive. Cov kev sib cuam tshuam no cuam tshuam los ntawm qhov sib npaug ntawm qhov zoo thiab tsis zoo modulators ntawm vasomotor tone ntawm afferent arterioles, uas tuaj yeem tsim los ntawm macula densa thiab tubular cells. TSIS MUAJ (nitric oxide)cuam ​​tshuamlub raummyogenic teb thiab TGF nrog rau lawv cov kev sib cuam tshuam, tab sis lub hauv paus ntawm NO (nitric oxide)tiam no tseem sib cav.

Medullary ntshav khiav thiab siab natriuresis Theraummedulla yog perfused los ntawm cortical arterioles thiab vasa recta capillary system ntawm juxtamedullary nephrons. Kev ntsuas ntawm cov ntshav medullary yog qhov nyuaj ntau dua li kev ntsuas ntawm cov ntshav cortical, uas tuaj yeem piav qhia qee yam ntawm cov txiaj ntsig sib txawv txog kev ua haujlwm ntawm medullary autoregulation hauv ntau cov kev tshawb fawb thiab hom. Cov nqes vasa recta yog ib puag ncig los ntawm kev cog lus pericytes uas tuaj yeem tsim cov lus teb myogenic8. Cov lus teb sib txawv autoregulatory tau piav qhia hauv tib neeg sab nraud medullary nqis vasa recta ntawm cov kab sib txawv. Hauv cov kab loj-ntev, kev cog lus tau pom nyob rau hauv cov lus teb kom nce luminal siab, whereas TSIS (nitric oxide)Kev hloov pauv tseem ceeb tau pom nyob rau hauv cov neeg uas muaj lub taub me me. Tib txoj kev tshawb fawb pom tau tias muaj kev sib haum xeeb-nyob ntawm qhov qis ntawm vasa recta hauv kev teb rau Ang II. NOS inhibition kuj tau pom tias ua rau muaj kev cuam tshuam ntawm cov nas uas nyob ib leeg los ntawm vasa recta; qhov vasoconstriction no tuaj yeem thim rov qab los ntawm NO (nitric oxide)pub los yog los ntawm pharmacological inhibition ntawm oxidative kev nyuaj siab siv NOX inhibitor los yog superoxide dismutase mimetic87.

Paracrine agents suav nrog NO (nitric oxide), prostaglandins, thiab ATP tau thov kom hloov kho medullary autoregulatory thiab siab natriuretic teb. Hauv cov nas juxtamedullary nephron npaj, inhibition ntawm macula densa nNOS ua rau muaj kev nce ntxiv hauv afferent arteriolar myogenic contraction nyob rau hauv cov lus teb rau nce perfusion siab 1,889. Los ntawm qhov sib txawv, stimulation ntawm NO (nitric oxide)ntau lawm nyob rau hauv cov nephron npaj dampened siab-induced contraction ntawm cortical radial artery thiab afferent arterioles los ntawm kev txo cov lus teb autoregulatory.

Muaj ob lub ntsiab hypotheses hais txog kev sib cuam tshuam ntawmlub raumautoregulation thiab siab natriuresis nyob rau hauv teb rau ncelub raumperfusion siab nrog zoo heev autoregulation ntawm cortical ntshav txaus nyob rau hauv lub xub ntiag los yog tsis muaj peev xwm autoregulation ntawm medullary ntshav txaus. Qhov sib txawv loj ntawm cov kev xav no cuam tshuam txog kev kho kom haum xeeb thiab qhov tseem ceeb ntawm kev hloov pauv hauv thawjlub raumcor-tical NO (nitric oxide)tiam piv rau qhov kev hloov pauv hauv cov ntshav medullary. Feem ntau, txoj kab nqes ntawm natriuretic teb kom ncelub raumperfusion siab yog attenuated los ntawm inhibition ntawm NOS. Ntxiv mus, nce RAAS kev ua ub no, kev ua siab zoo paj hlwb thiab kev tsim ntau dhau ntawm ROS, tshwj xeeb tshaj yog nyob rau hauvraummedulla, tuaj yeem cuam tshuam lub siab natriuresis.

Abnormal NO (nitric oxide)homeostasis ua ke nrog nce hauv Ang I thiab ROS thiab anomalouslub raumautoregulation (xws li kev ua kom muaj zog ua rau muaj kev ntxhov siab lossis txo qis hauv lub xeev mob) tau pom nyob rau hauv kev sim ua qauv ntawm kev kub siab (piv txwv li, spontaneously hypertensive nas, Milan hypertensive strain ntawm nas, Dahl ntsev-sensitive nas, Goldblatt renovascular hypertension, Ang II-induced hypertension, DOCA- ntsev hypertension, xim av Norway nas), CKD (piv txwv li, txolub raumcov qauv loj) thiab T2DM (piv txwv li, rog Zucker mob ntshav qab zib nas thiab noj zaub mov muaj roj ntau). Ua ke, cov kev tshawb fawb no qhia tias augmentedlub raumautoregulation (tshwj xeeb yog TGF) tuaj yeem pab txhawb kev txhim kho ntshav siab, thaum txo qislub raumautoregulation tuaj yeem ua rau ob qho tib si mob ntshav siab thiab mob ntshav qab zib nephropathies.

Daim duab 4|teebmeem ntawm No (nitric oxide)ntawm sodium transporters hauv nephron.

Nitric oxide(NO) feem ntau suav hais tias yog inhibit tubular sodium reabsorption raws nephron. Txawm li cas los xij, cov txiaj ntsig sib txawv tau txais nyob rau hauv cov mob hnyav thiab mob ntev, hauv kev sim sib txawv (hauv vivo piv rau ex vivo lossis hauv vitro) thiab ntau hom. Ntxiv mus, cov teebmeem ntawm NO (nitric oxide)ntawm tubular sodium (Na plus) tuav zoo li yog nyob ntawm kev ua haujlwm hormonal, tshwj xeeb tshaj yog los ntawm kev cuam tshuam nrog renin-angiotensin-aldosterone system. Nyob rau hauv lub proximal tubule, neuronal NO (nitric oxide)synthase (nNOS) thiab endothelial NOS (eNOS)-derived NO tau raug tshaj tawm los inhibit basolateral sodium-potassium twj tso kua mis (Na plus / K ntxiv -ATPase) thiab apical sodium / hydrogen exchanger 3 (NHE3), nrog rau kev hloov pauv. Kev ua haujlwm ntawm basolateral Na plus / HCO3- cotransporter. Nyob rau hauv tuab ascending limb (TAL) ntawm lub voj ntawm Henle, eNOS-derived NO (nitric oxide)inhibits NHE3 thiab kuj tseem tuaj yeem cuam tshuam cov apical Na plus -K ntxiv rau -2Cl− cotransporter (NKCC2). eNOS-derived NO kuj inhibits NKCC2 hauv macula densa hlwb. Kev ua kom nNOS hauv macula densa tuaj yeem cuam tshuam cov teeb liab paracrine sib kho los ntawm adenosine triphosphate (ATP) thiab adenosine (ADO), uas yog ib feem ntawm tubuloglomerular tawm tswv yim mechanism tom qab ua kom muaj purinergic P2 thiab / lossis adenosine A1 receptors nyob rau ntawm vascular du leeg hlwb hauv lub afferent arteriole. nNOS qhia tau pom nyob rau hauv lub distal tubule tab sis muaj peev xwm los ntawm NO (nitric oxide)Ntawm cov neeg thauj khoom tshwj xeeb hauv ntu ntawm nephron (piv txwv li, Na plus / Cl- cotransporter) tam sim no tsis meej. Thaum kawg, hauv kev sau cov kab hluav taws xob, nNOS-derived NO (nitric oxide)tuaj yeem inhibit qhov epithelial sodium channel (ENaC).

NYEEM NO PART Ⅱ