Ntu Ⅰ: Lub Pathology Ntawm Aldosterone Biosynthesis Thiab Nws Ua
Apr 14, 2023
Abstract
Aldosterone plays lub luag haujlwm tseem ceeb hauv renin-angiotensin-aldosterone system kom tswj cov kua dej ntim thiab electrolyte metabolism homeostasis. Qhov kev txiav txim ntawm aldosterone yog kho los ntawm mineralocorticoid receptor thiab 11 -hydroxysteroid dehydrogenase hom 2 (11 -HSD2). Nws qhov kev ua ntau dhau tuaj yeem ua rau cov ntaub so ntswg puas hauv lub cev, xws li myocardial thiab vascular fibrosis, ntxiv rau cov kab mob raum, ncaj qha. Kev ua aldosterone ntau dhau kuj tau tshaj tawm tias muaj feem cuam tshuam nrog qhov tsis txaus ntawm cov metabolism hauv electrolyte hauv cov kab mob plab hnyuv thiab kev loj hlob ntawm cov kab mob pulmonary. Aldosteronism yog thawj zaug faib ua thawj thiab theem nrab. Primary aldosteronism muaj ntau dua thiab paub tias ua rau muaj ntshav siab ntxiv thiab ua rau cov hlab plawv tom qab. Primary aldosteronism kuj tau muab faib ua ntau hom subtypes, nrog rau aldosterone-tsim adenomas yog qhov ntau tshaj plaws thiab suav rau feem ntau ntawm unilateral thawj aldosteronism. Bilateral aldosteronism yog dominated los ntawm diffuse aldosterone-tsim hyperplasia thiab me me aldosterone-tsim nodules los yog nodules ua lub ntsiab subtypes. Tag nrho cov kab mob uas ua rau aldosterone no tau raug tshaj tawm tias muaj kev hloov pauv ntawm somatic xws li KCNJ5, CACNA1D, ATP1A1, thiab ATP2B3, tag nrho cov uas cuam tshuam nrog ntau tshaj aldosterone ntau lawm. Ntawm cov kev hloov pauv saum toj no, kev hloov pauv ntawm somatic hauv KCNJ5 feem ntau tshwm sim hauv aldosterone-tsim adenomas thiab feem ntau yog tsim los ntawm cov hlwb ntshiab nrog kev nthuav qhia ntau ntawm aldosterone synthase. Nyob rau hauv sib piv, cacna1d kev hloov nyob rau hauv aldosterone-tsim nodules los yog aldosterone-tsim nodules yog nquag pom tsis tau tsuas yog nyob rau hauv cov neeg mob nrog thawj hyperaldosteronism tab sis kuj nyob rau hauv lub glomerular cheeb tsam ntawm ib txwm qog adrenal, uas tej zaum yuav nws thiaj li ua rau autonomous aldosterone ntau lawm uas ua rau ib txwm los yog pom tseeb thawj. hyperaldosteronism, tab sis cov ntsiab lus tseem tsis meej.
Ntsiab lus
aldosterone; 11 -hydroxysteroid dehydrogenase; mineralocorticoid receptors; pathology; thawj aldosteronism;Cistanche extract.
Nyem qhov no mus yuavCistanche ntxiv
Taw qhia
Aldosterone yog ib feem tseem ceeb ntawm renin-angiotensin-aldosterone system (RAAS), tswj homeostasis ntawm cov kua ntim thiab electrolyte metabolism (Laragh li al. 1972, Laragh thiab Sealey 2011, Patel et al. 2017), thiab yog tsim nyob rau hauv lub adrenal. glomerular zone (ZG) ntawm lub cortex. Aldosterone tuaj yeem khi rau cov mineralocorticoid receptor (MR) thiab tswj cov dej, sodium, thiab potassium reabsorption (Booth li al. 2002; Nakamura li al. 2016; Seccia li al. 2018). Txawm li cas los xij, MR tuaj yeem qhib tsis tau tsuas yog los ntawm mineralocorticoids xws li aldosterone tab sis kuj los ntawm glucocorticoids, suav nrog cortisol thiab corticosterone, vim tias lawv muaj kev sib raug zoo zoo sib xws rau MR (Krozowski thiab Funder 1983; Arriza li al. 1987; Sheppard thiab Funder). Yog li, 11 -hydroxysteroid dehydrogenase hom 2 (11 -HSD2) plays lub luag haujlwm tseem ceeb hauv kev sib tham txog mineralocorticoid tshwj xeeb los ntawm qhov chaw degradation ntawm cortisol lossis hloov pauv ntawm cortisol rau cortisone, thiab cov enzyme no muaj kev cuam tshuam me ntsis rau MR thiab , raws li qhia los ntawm peb pab pawg, co-localizes nrog MR nyob rau hauv yuav luag tag nrho cov tib neeg cov ntaub so ntswg (Edwards li al. 1988; Funder li al. 1988; Hirasawa li al. 1997,1999,2000; Stewart li al. 1987; Suzuki li al. 1998; Takahashi et al. 1998). Tsis tas li ntawd, aldosterone tau raug tshaj tawm tias muaj feem cuam tshuam rau kev ua haujlwm ntawm ntau yam kabmob uas tsis yog lub raum, suav nrog cov ntaub so ntswg, vascular du nqaij, plab, lacrimal qog, hws qog, thiab bronchial epithelium, thiab kom muaj kev cuam tshuam los yog cuam tshuam rau cov kabmob uas tau hais tseg. .
Autonomous overproduction ntawm aldosterone los yog thawj aldosteronism (PA) yog feem ntau txuam nrog somatic kev hloov nyob rau hauv cov noob nrog rau cov poov tshuaj nyob rau hauv rectifier channel subfamily J tus tswv cuab 5 (KCNJ5), calcium voltage-gated channel subunit 1D (CACNA1D), ATPase Na ntxiv / K ntxiv thauj subunit 1 (ATP1A1), thiab ATPase plasma membrane Ca2 ntxiv rau thauj 3 (ATP2B3) muaj feem xyuam (Zennaro li al., 2017). Tsis tas li ntawd, cov kev hloov pauv ntawm somatic no feem ntau pom nyob rau hauv ib sab lossis ob sab aldosterone-tsim adenomas (APA), aldosterone-producing microspheres (APM), thiab aldosterone-producing nodules (APN), tag nrho cov uas yuav ua rau cov ntshav siab los yog kho mob tseem ceeb PA. , txawm tias lawv cov ntsiab lus tseem tsis paub. Yog li ntawd, nws yog ib qho tseem ceeb los qhia cov ntsiab lus hauv qab no ntawm qhov kev sib tshuam no; 1. aldosterone ua rau ntau yam ntaub so ntswg thiab ua lub luag haujlwm tseem ceeb hauv lawv cov kab mob pathology; thiab 2. PA yog ib yam mob uas yuav tsum tau kuaj thiab kho nyob rau theem kho mob thaum ntxov kom tsis txhob muaj kev puas tsuaj rau lub cev tam sim ntawd thiab recalcitrant. Yog li ntawd, tsab xov xwm no muab kev tshuaj xyuas ntawm pathophysiology ntawm aldosterone biosynthesis thiab nws lub luag haujlwm nrog rau cov pathology ntawm PA.
Lub luag haujlwm ntawm lub cev ntawm aldosterone hauv renin-angiotensin-aldosterone system (RAAS)
RAAS ua lub luag haujlwm tseem ceeb hauv kev tswj hwm ntawm cov khoom ntim ntxiv, sodium-potassium tshuav nyiaj li cas, thiab vascular system tone hauv tib neeg lub cev lub cev. Thawj kauj ruam hauv RAAS yog kev sib txuas ntawm angiotensinogen hauv daim siab. Angiotensinogen yog tom qab hloov mus rau angiotensin (Ang) I los ntawm kev ua kom renin, uas yog tswj los ntawm lub raum siab receptors thiab sodium chloride (NaCl) thauj hauv glomerular paracellular apparatus mus rau ntom macula. Yog li, kev hloov pauv hauv cov ntshav siab thiab qhov sib npaug ntawm electrolyte tuaj yeem ua rau nce renin ntau lawm, ntxiv rau kev hloov pauv ntawm angiotensinogen rau Ang I raws li tus nqi-txheej theem hauv lub cev. Ang I tom qab hloov mus rau Ang II ntawm angiotensin-hloov enzyme (ACE), thiab ACE yog dav tso tawm los ntawm cov hlwb endothelial lossis lwm cov hlwb. ACE-2 tau raug tshaj tawm los hloov Ang II mus rau lwm qhov isoform ntawm RAAS peptide Ang-(1- 7), uas txo qis Ang II thiab xav tias yog cov khoom degradation ntawm Ang II. Ang II khi rau angiotensin II hom 1 receptor (AT1R) hauv adrenocortical ZG, uas tom qab ntawd ua rau kev yooj yim ntawm aldosterone biosynthesis.AT2R xav tias yog lwm isoform uas antagonizes AT1R kom txo cov ntshav siab. Yog li, AT1R-stimulated aldosterone nce siab yog qhov tseem ceeb tshaj plaws hauv RAAS, ua rau muaj kev tswj hwm ntawm sodium thiab kua ntim, nrog rau lub raum poov tshuaj tso tawm. Aldosterone kuj khi rau cov mineralocorticoid receptor (MR) thiab nce cov kev ua ntawm tubulointerstitial Na ntxiv cov channels (ENaC), tubulointerstitial K ntxiv cov channel, thiab plasma membrane Na plus / K ntxiv -ATPase. Tsis tas li ntawd, dej ua raws li tus ntoo khaub lig-cellular txav ntawm Na ntxiv thiab tswj qhov sib npaug ntawm cov kua hauv lub cev.
Herba Cistanche
Aldosterone biosynthesis hauv adrenocortical ZG
Hauv adrenocortical ZG, Ang II khi rau AT1R yog ua raws li kev tsim cov inositol 1,4, 5-trisphosphate (IP3) thiab diacylglycerol (DAG) tom qab inositol-specific phospholipase C (PLC) ua kom. Activated IP3 ua rau muaj kev nce ntxiv hauv cov calcium hauv lub cev, uas tig mus ua kom cov calcium / calmodulin-dependent protein kinase (CaMK) thiab thaum kawg txhawb kev qhia ntawm aldosterone biosynthesis nyob rau hauv ib txwm adrenal ZG los ntawm activating cAMP teb cov ntsiab lus khi (CREB). Ob qho ntawm cov xwm txheej no nce cytoplasmic Ca thiab DAG ua kom muaj protein ntau kinase C (PKC), uas ua rau cov protein kinase D (PKD) kom qhib CREB los txhawb cov steroidogenic acute regulatory protein (StAR) transcription, uas nyob rau hauv lem nce CYP11B2 qhia theem (Daim duab 1).
Zoo li lwm yam corticosteroids, cov roj (cholesterol) yog qhov ua ntej rau aldosterone thiab tom qab ntawd hloov mus rau pregnenolone (CYP11A1) thaum ua kom los ntawm cytochrome P450 sab saw cleavage. Pregnenolone ces hloov mus rau progesterone los ntawm 3 -hydroxysteroid dehydrogenase (3 - HSD). 21-hydroxylase (CYP21A2) catalyzes hloov ntawm progesterone rau deoxycorticosterone thiab aldosterone synthase (CYP11B2) thaum kawg catalyzes nws hloov dua siab tshiab rau aldosterone. Ntawm qhov tod tes, cortisol yog tsim nyob rau hauv lub zona fasciculate (ZF) los ntawm ib tug cascade ntawm ntau yam tshuaj hormones tsim enzymes stimulated los ntawm adrenocorticotropic hormone (ACTH). Cov enzymes koom nrog hauv kev hloov cov roj cholesterol mus rau 11-deoxycortisol suav nrog CYP11A1, 17- -hydroxylase/17,20 lyase (CYP17A1), thiab HSD3B. Cortisol yog qhov kawg biosynthesized nyob rau hauv kev ua kom ntawm 11 -hydroxylase (CYP11B1) (Daim duab 1).
Cov kab mob qog adrenal uas ua rau aldosterone
Peb tsis ntev los no tau pom tias nyob rau hauv feem coob ntawm tib neeg lub cev adrenals, aldosterone tsis tas yuav tsim tawm, tab sis nyob rau hauv ZG nyob rau hauv daim ntawv ntawm aldosterone-producing micronodules (APMs), yav tas los hu ua aldosterone-producing cell pawg (APCCs).APMs. txhais tau tias yog CYP11B2-ZG hlwb zoo nyob rau hauv lub hnab ntawv adrenal, uas feem ntau tsawg dua 10 mm nyob rau hauv txoj kab uas hla siab tshaj plaws thiab tsuas tuaj yeem txheeb xyuas los ntawm Tsis yog CYP11B1 lossis CYP17A1 immunoreactivity muaj nyob rau hauv cov APMs no. Hauv kev sib piv rau CYP11B2 tau piav qhia saum toj no, cov steroidogenic enzymes tseem ceeb suav nrog CYP17A1 thiab CYP11B1 tau nthuav dav dav hauv qhov qub zona fasciculata (ZF). Tsis tas li ntawd, peb tsis ntev los no tau tshaj tawm tias tus naj npawb ntawm APMs hauv ib txwm ZG nce nrog hnub nyoog. Txawm li cas los xij, raws li tus naj npawb ntawm APMs tau nce, tag nrho cov naj npawb ntawm CYP11B2- thaj chaw zoo hauv APMs kuj pom qhov cuam tshuam tsis zoo nrog hnub nyoog. Ua ke, cov txiaj ntsig no qhia tias RAAS-ywj siab APMs nrog ntau tus kheej tswj hwm thiab tsis tshua muaj lub cev aldosterone ntau lawm tau xav tias yuav cuam tshuam nrog kev laus, qhov chaw focal lossis localized nodal aldosterone ntau lawm hauv ZG kuj tuaj yeem xav tias sawv cev rau kev hloov pauv ntawm cov qog adrenal. Peb yuav tham txog cov teeb meem no tom qab hauv daim ntawv no.
Standardized Cistanche
11 -Hydroxysteroid Dehydrogenase Hom 2 (11 -HSD2)
11 -HSD kho aldosterone kev ua hauv tib neeg cov ntaub so ntswg
Raws li tau hais los saum no, aldosterone ua los ntawm kev khi rau MR hauv lub raum, txoj hnyuv, cov qog ua kua qaub, thiab lwm yam kabmob. Txawm li cas los xij, cov txiaj ntsig ntawm kev tshawb fawb hauv vitro ntxov qhia tias MR kuj muaj qhov sib xws rau glucocorticoids (xws li cortisol thiab corticosterone). Yog li ntawd, nws yog kev ntxias kom xav tias nyob rau hauv lub cev nqaij daim tawv uas cov ntshav cortisol ntau dua li aldosterone, MR tuaj yeem ua haujlwm tsis tu ncua los ntawm cortisol thiab aldosterone cov teebmeem tshwj xeeb tsis zoo li tshwm sim hauv tib neeg. Txawm li cas los xij, tom qab kev tshawb pom tau qhia tias MR tau xaiv los ntawm picomolar qib ntawm aldosterone hauv lub raum lub raum hauv vivo, tab sis tsis yog los ntawm ntau dua nanomolar qib ntawm cortisol. Yog li, qhov sib txawv ntawm kev sib txuas ntawm aldosterone thiab cortisol rau MR hauv vivo thiab kev tshawb fawb hauv vitro muab cov lus nug nthuav tab sis tsis txaus ntseeg txog cov txheej txheem ntawm kev ua ntawm aldosterone. Ib tug xov tooj ntawm cov lus pom zoo tau nthuav tawm keeb kwm los piav qhia qhov sib txawv loj ntawm cov lus hais saum toj no hauv vitro thiab hauv vivo tshawb pom. Piv txwv li, aldosterone tau thov kom hla cov cell membranes hauv ib qho tshwj xeeb tshaj li cortisol, los yog qee qhov kev tsis paub yuav tshwm sim los hloov cov tshuaj hauv cov cell ntawm ob qho tshuaj hormones (aldosterone thiab cortisol). Qhov tsis sib xws tsis txaus ntseeg no thaum kawg tau daws los ntawm cov kev tshawb fawb ntxaws ntxaws ntawm cov kab mob tsawg. Qhov tsis muaj kev hloov pauv ntawm cortisol mus rau cortisone tau tshaj tawm hauv cov ntaub ntawv kho mob. Qhov no tsis tshua muaj kab mob caj ces, tseem hu ua qhov pom tseeb mineralocorticoid ntau dhau syndrome, tau tshaj tawm hauv cov menyuam yaus uas pom tias muaj ntshav siab, sodium retention, poov tshuaj poob, thiab kev tawm tsam ntawm plasma renin kev ua si txawm tias tsis tuaj yeem kuaj pom cov qib mineralocorticoid. Cov kev soj ntsuam tom qab tau qhia tias cortisol nws tus kheej ua raws li mineralocorticoid hauv cov neeg mob no. Tom qab ntawd, nws tau tshaj tawm tias dexamethasone inhibition ntawm endogenous cortisol thim rov qab ntau yam tsos mob vim mineralocorticoid overdose, thiab cov tsos mob zoo li no txawm tias tom qab txiav tawm ntawm kev kho dexamethasone. lub tswv yim tsis meej ntawm qhov tsis tshua muaj tab sis qhov tshwj xeeb ntawm caj ces thaum kawg tau qhia meej nyob rau xyoo 1980s los ntawm kev kawm txog kev ua ntawm 11 -hydroxysteroid dehydrogenase (11 -HSD) thiab cov xwm txheej ntawm cov enzyme no, MR unbound affinity nyob rau hauv ntau yam aldosterone. Lub hom phiaj cov ntaub so ntswg txhais cov aldosterone tshwj xeeb hauv vivo. Hauv lub raum, 11 -HSD catalyzes cortisol thiab corticosterone rau cortisone thiab 11 -dehydrocortisone, raws li, ob qho tib si tsis muaj peev xwm khi rau MR. Tsuas yog aldosterone, uas tsis yog catalyzed los ntawm 11 -HSD, tuaj yeem khi MR thiab thaum kawg tsim cov tshuaj hormone tshwj xeeb hauv cov ntaub so ntswg hauv vivo.
Lub isozyme ntawm 11 -HSD: hom 1 thiab hom 2
Txawm li cas los xij, nrog kev tshawb pom ntawm lub luag haujlwm muaj peev xwm rau 11 -HSD enzyme hauv mineralocorticoid kev txiav txim, qee qhov kev pom tsis sib haum lossis tsis sib haum kuj tau tshaj tawm. Piv txwv li, 11 -HSD feem ntau tshwm sim hauv daim siab, tab sis lub siab nws tus kheej tsis muaj MR nyob rau hauv ob hom cell. Ntxiv rau, 11 -HSD tsis tas yuav koom nrog MR hauv lub raum lub raum. Cov txiaj ntsig saum toj no qhia tias 11 -HSD yuav muaj nyob ua ib qho isozyme. Cov kev tshawb fawb txuas ntxiv kuj tau qhia txog qhov muaj nyob ntawm isozyme tshiab lossis isoform hu ua 11 hsd hom 2 (11 - HSD2) ntxiv rau daim ntawv qub, 11 hsd hom 1 (11 -HSD1). 11 -HSD2 tuaj yeem metabolize cortisol rau cortisone thiab tsis tuaj yeem sib tw nrog Mr. khi rau aldosterone thiab saum toj no 11 - HSD1 tuaj yeem cuam tshuam kev hloov pauv ntawm cortisol mus rau cortisol nquag. 11 - HSD1 yog dav faib nyob rau hauv tib neeg cov ntaub so ntswg, xws li lub siab, vascular system, adipose ntaub so ntswg, zes qe menyuam, testes, thiab hlwb. Tom qab ntawd, peb siv dual immunohistochemistry thiab/los yog immunohistochemical tsom xam siv ib tug series ntawm daim iav ntaub so ntswg seem los qhia tias 11 -HSD2 co-localizes tshwj xeeb nrog MR nyob rau hauv yuav luag tag nrho cov aldosterone lub hom phiaj cov ntaub so ntswg, xws li raum, lub plawv nqaij, vascular du nqaij, plab hnyuv, lacrimal caj pas, hws caj pas, bronchial epithelium, thiab lwm yam ntaub so ntswg. Tom qab ntawd peb tau ua pov thawj tias 11 -HSD2 ua lub luag haujlwm tseem ceeb tsis yog hauv kev ua haujlwm ntawm lub cev thiab kev ua haujlwm ntawm aldosterone hauv tib neeg lub cev. Hauv seem tom ntej no, peb yuav tham ntxiv txog lub luag haujlwm pathophysiological ntawm qhov kev cai hauv zos txaus nyiam ntawm aldosterone.
cov txiaj ntsig ntawm Cistanche cov txiaj ntsig
Pathology ntawm Aldosterone Kev Ua
Aldosterone Kev Ua Haujlwm hauv inflammatory plob tsis so tswj kab mob
Aldosterone tuaj yeem tswj hwm Na plus reabsorption los ntawm kev khi rau MR hauv colonic epithelial hlwb. Tsis tas li ntawd, cov kab mob plab hnyuv loj (IBD) suav nrog cov kab mob ulcerative colitis lossis Crohn tus kab mob tau raug tshaj tawm tias muaj kev cuam tshuam ntawm epithelial Na plus absorption. Ulcerative colitis yog tus cwj pwm los ntawm cov kab mob inflammatory ntawm lub qhov quav mucosa los ntawm qhov quav mus rau txoj hnyuv, txawm hais tias muaj ntau qhov kev zam tau tshaj tawm nyob rau hauv ib qho kev pheej hmoo. Ntawm qhov tod tes, Crohn tus kab mob txhais tau tias yog cov kab mob transmural uas tuaj yeem cuam tshuam rau ib feem ntawm lub plab hnyuv ntawm lub qhov ncauj mus rau qhov quav, tsis tas yuav tsum tau ua tas mus li). Cov kev tshawb pom saum toj no qhia tias aldosterone tuaj yeem koom nrog hauv IBD, tshwj xeeb tshaj yog nyob rau hauv kev cuam tshuam rau kev kho mob raws plab, xav txog qhov tseem ceeb ntawm aldosterone hauv kev tswj hwm txoj haujlwm ntawm plab hnyuv. Peb tau lees paub qhov kev qhia ntawm 11 -HSD2 nyob rau hauv ib txwm colonic mucosa, ulcerative colitis, thiab Crohn's disease. Nyob rau hauv ib txwm colonic mucosa, ib tug ntshiab gradient ntawm 11 -HSD2 qhia tau pom nyob rau hauv lub colonic epithelium thiab colonic crypt, piv txwv li, ntau pronounced diffusion rau mucosal nto. Txawm li cas los xij, 11 -HSD2 tau txo qis lossis txawm tias tsis nyob hauv cov hlwb epithelial nyob ib puag ncig cov kab mob hnyav hauv cov kab mob ulcerative. Tsis tas li ntawd, ob qho tib si protein thiab mRNA qib ntawm 11 -HSD2 tsis tau qhia lossis raug txo qis hauv cov kab mob ulcerative piv nrog cov kab mob colonic epithelial uas nyob ib sab ntawm cov mucosa uas tsis muaj mob. Ntawm qhov tseem ceeb, kuj tsis muaj qhov sib txawv tseem ceeb hauv 11 -HSD2 qhia ntawm cov neeg mob uas muaj kab mob plab uas tau txais cov tshuaj corticosteroids ua ntej thiab cov uas tsis ua. Qhov kev tshawb pom nthuav dav no qhia tau hais tias kev kho glucocorticoid ntawm cov neeg mob uas muaj kab mob ulcerative colitis muaj kev cuam tshuam me ntsis rau kev nthuav qhia ntawm 11 -HSD2 hauv cov kab mob hauv cov kab mob colonic epithelial. Kev txo qis ntawm 11 -HSD2 kev qhia hauv cov kab mob ulcerative colitis kuj tau tshaj tawm tias yuav kho los ntawm cov cytokines pro-inflammatory, xws li qog necrosis factor (TNF)- thiab interleukin (IL)-1, los ntawm kev tshawb fawb hauv vitro thiab nas qauv. Hauv cov ntsiab lus, ulcerative colitis inflammatory cells tuaj yeem kho qhov kev qhia ntawm 11 -HSD2 los ntawm ob qho tib si transcriptional thiab translational pathways, ua rau txawv txav ntawm dej thiab Na ntxiv rau cov neeg mob, ua rau mob raws plab. Cov kev tshawb pom saum toj no tau tso lub teeb tshiab rau ntawm pathophysiology ntawm cov neeg mob ulcerative colitis.
