Kev sib deev Dimorphism Ntawm Corticosteroid Signaling Thaum lub raum loj hlob

Abstract:Kev sib deev dimorphism cuam tshuam qhov sib txawv ntawm kev sib deev lom neeg uas mus dhau qhov kev sib deev. Hauv cov tsiaj nyeg, qhov sib txawv ntawm poj niam txiv neej tau qhia txog ntau yam kev lom neeg, nrog rau cov ntshav siab thiab predisposition los tsim cov ntshav siab thaum ntxov rau cov neeg laus, uas tuaj yeem tso siab rau cov xwm txheej thaum ntxov thaum loj hlob thiab lub sij hawm neonatal. Cov kev tshawb fawb tsis ntev los no qhia tias corticosteroid signaling pathways (suav nrog glucocorticoid thiab mineralocorticoid signaling pathways) muaj cov ntaub so ntswg tshwj xeeb qhia thiab kev tswj hwm thaum lub sijhawm tshwj xeeb ntawm lub cev ntawm lub cev hauv kev sib deev, tshwj xeeb tshaj yog nyob rau hauvraum. Qhov kev tshuaj xyuas no qhia txog cov pov thawj rau kev qhia txog poj niam txiv neej sib txawv thiab ua kom lub raum corticosteroid qhia txoj hauv kev hauv cov menyuam hauv plab mammalian thiab neonate, los ntawm nas mus rau tib neeg, uas yuav nyiam cov teeb liab mineralocorticoid rau cov poj niam thiab cov cim qhia glucocorticoid hauv cov txiv neej. Kev txiav txim siab qhov cuam tshuam ntawm qhov sib txawv no tuaj yeem ua rau pom qhov tshwm sim rau lub sijhawm luv thiab ntev ntawm cov kab mob pathophysiological, ua rau cov txiv neej.

Ntsiab lus:aldosterone; cortisol; mineralocorticoid thiab glucocorticoid receptors; cov me nyuam mos;raum; kev loj hlob;kev sib deevdimorphism

Hu rau: ali.ma@wecistanche.com

Nyem rau maca ginseng cistanche hiav txwv nees rau lub raum ua haujlwm

1. Taw qhia

Corticosteroids (mineral corticosteroids thiab glucocorticosteroids) yog cov tshuaj hormones tseem ceeb uas cuam tshuam rau kev ua haujlwm ntawm ntau cov ntaub so ntswg kom tswj hwm homeostasis. Lawv cov haujlwm tseem ceeb vam khom rau lawv txoj kev khi rau Mineralocorticoid thiab Glucocorticoid receptors (MR thiab GR, feem). Cov kev tshawb fawb tsis ntev los no tau hais txog lub qhov rais ntawm lub cev thaum lub sijhawmraumtxoj kev loj hlob, uas yog zoo-conserved ntawm cov tsiaj, qhov twg corticosteroid signaling pathways muaj ib tug tshwj xeeb qauv ntawm kev qhia thiab kev cai, nyob rau hauv kev sib raug zoo mus rau lub adaptation ntawm tus me nyuam hauv plab thiab cov me nyuam mos, hloov ntawm dej mus rau ib qho chaw huab cua. Qhov kev tshuaj xyuas no yuav xub nthuav qhia luv luv ntawm mineralocorticoid thiab glucocorticoid kev taw qhia txoj hauv kev (los ntawm aldosterone thiab cortisol biosynthesis rau cov txheej txheem ntawm kev tswj hwm thiab kev ua ntawm MR thiab GR) thaum lub sijhawmraumkev loj hlob. Kev qhia tshwj xeeb yuav raug muab tso rau hauv cov kev tshawb fawb tsis ntev los no qhia txog kev sib deev dimorphic qhia, uas tej zaum yuav muaj kev cuam tshuam rau pathophysiological, tshwj xeeb tshaj yog nyob rau hauv cov txiv neej / cov tub, uas muaj kev nyuaj siab ntxiv thaum lub sij hawm cev xeeb tub thiab muaj kev pheej hmoo siab ntawm kev mob ntshav siab thaum ntxov hauv lub neej.

2. Mineralocorticoid Signaling Pathway

2.1. Kev cai ntawm Aldosterone Synthesis

Aldosterone, steroid hormone secreted los ntawm Zona Glomerulosa (ZG), txheej txheej ntawm lub qog adrenal cortex, yog qhov tseem ceeb rau kev tswj lub cev kua dej thiab electrolyte homeostasis, los ntawm sodium tuav thiab yog li tswj ntshav siab [1]. Raws li adrenal ZG tsis muaj peev xwm khaws aldosterone ib zaug nws tau tsim, cov kev cai ntawm nws cov secretion yog inextricably txuas mus rau transcriptional activation thiab post-transcriptional modifications ntawm steroidogenic enzymes. Mob aldosterone ntau lawm yog tswj los ntawm cov txheej txheem thaum ntxov ntawm cov cholesterol uptake thiab hloov dua siab tshiab rau pregnenolone uas yog kho los ntawm kev nthuav qhia thiab phosphorylation ntawm steroidogenic mob hnyav regulatory protein, StAR (encoded los ntawm STAR noob). Ib txoj kev cai lig dhau los tswj cov kev qhia ntawm biosynthesis enzymes, tshwj xeeb tshaj yog CYP11B2 (aldosterone synthase, encoded los ntawm CYP11B2 gene), tswj cov kab mob aldosterone ntau lawm [2]. Aldosterone biosynthesis nyob rau hauv ZG yog physiologically tswj los ntawm Angiotensin II (Ang II), poov tshuaj (K ntxiv), thiab kom tsawg dua los ntawm AdrenoCorticoTropic Hormone (ACTH). Lwm yam bioactive compounds (serotonin, leptin, endothelin, nitric oxide, catecholamines, atrial natriuretic peptide, neuropeptide tshuaj P) raug tso tawm los ntawm adipocytes, mast hlwb, chromaffin hlwb, los yog paj hlwb xaus nyob ze ZG hlwb kuj tau pom los txhawb aldosterone secretion [ 3, 4] ib. Stimulation ntawm Renin-Angiotensin System (RAS) yog pib los ntawm kev ua kom muaj kev sib haum xeeb, txo qis perfusion siab hauv lub raum afferent arterioles, lossis txo cov ntsiab lus sodium hauv macula densa ntawm lub raum distal tubules, uas ua rau kev tso tawm ntawm renin los ntawm juxtaglomerular cells. . Tom qab ntawd, renin converts circulating angiotensinogen tsim los ntawm lub siab mus rau angiotensin I (Ang I), uas yog tom qab cleaved los ntawm Angiotensin-Converting Enzyme (ACE) los tsim octapeptide Ang II. Kev khi ntawm Ang II rau nws cov AT1 receptor (AT1R) ua rau kev tso tawm calcium los ntawm cov khw muag khoom hauv lub cev, uas yog qhov tseem ceeb ntawm kev txiav txim siab ntawm aldosterone secretion [3]. Kev nce me me hauv extracellular K ntxiv rau depolarize glomerulosa cell, kuj nce calcium influx los ntawm voltage-gated calcium raws uas txhawb CYP11B2 thiab Star transcription [5]. Thaum kawg, ACTH ib leeg txhawb nqa aldosterone secretion acutely thiab transiently tab sis kom tsawg dua li Ang II thiab K ntxiv. ACTH khi rau nws cov Melanocortin Receptor 2 (MC2R) txhawb kev qhia Star los ntawm kev ua kom adenylate cyclase [6]. Thaum lub sij hawm txoj kev loj hlob, fetal aldosterone ntau lawm tshwm sim nyob rau hauv lub meej cheeb tsam, uas yog tus counterpart ntawm ZG ntawm cov neeg laus adrenal cortex. Thaum StAR thiab lwm yam tseem ceeb enzymes qhia maj mam nce thaum cev xeeb tub [7], CYP11B2 qhia tsuas yog tshwm sim nyob ib ncig ntawm 24 lub lis piam gestational (GW) [8]; ces, nws nce mus txog thaum yug me nyuam zoo li cov neeg laus adrenal [9]. Lub plasma concentrations ntawm aldosterone muaj nyob rau hauv cov me nyuam yug ntxov ntxov ntxov li 25 GW [10], tab sis aldosterone ntau lawm tseem tsawg txog 30 GW [9]. Aldosterone concentration nce ntxiv tom qab ntawd kom txog thaum lub sijhawm [10], nyob rau hauv kev sib raug zoo rau fetal neo-synthesis [11]. Tsis muaj kev sib deev dimorphism tau tshwm sim txog ntshav plasma aldosterone qib hauv fetus lossis thaum yug [12].

2.2. Lub Mineralocorticoid Receptor (MR)

2.2.1. Gene, Transcripts, thiab Protein Variants

MR belongs rau lub nuclear receptor superfamily uas kho cov sodium-tso kev txiav txim ntawm aldosterone nyob rau hauv lub distal nephron [13]. Qhov kev hloov pauv no yog encoded los ntawm NR3C2 noob, uas nyob hauv tib neeg ntawm locus 4q31.1–4q31.2 [14,15] thiab encodes 984 amino-acids protein (≈107 kDa) [16], koom ua plaub qhov sib txawv. structural domains: N-terminal domain (NTD), DNA binding domain (DBD), thaj tsam pob khawm, thiab ligand-binding domain (LBD). MR kev ua haujlwm tau pom tias tau hloov kho los ntawm kev sib txawv ntawm qhov sib txawv, tsis muaj exon 6 lossis ob qho tib si exon 5 thiab 6 [17,18]. Ob qhov sib txawv loj ntawm tib neeg MR, hu ua MRA thiab MRB, yog tsim los ntawm lwm qhov chaw pib ntawm kev txhais lus los ntawm methionine 1 thiab 15, raws li. Cov MR variants no qhia txog qhov sib txawv ntawm kev ua haujlwm hauv vitro [19].

2.2.2. Mechanisms of Regulation of MR Expression and Activity

Ob txoj kev txhawb nqa txhawb nqa kev qhia ntawm NR3C2 gene [20], proximal P1 proximal proximal, uas yog transcriptionally active nyob rau hauv tag nrho cov MR lub hom phiaj cov ntaub so ntswg, thiab lub distal P2 promoter, uas yog weaker thiab transcriptionally active nyob rau hauv lub hauv paus paj hlwb thaum lub sij hawm tshwj xeeb kev loj hlob theem los yog physiological xwm txheej [21]. Ntawm qhov kev txaus siab tshwj xeeb, qhov kev qhia ntawm no cov receptor nuclear, uas hloov pauv tswj dej thiab sodium tshuav nyiaj li cas, kuj tseem tswj hwm ntawm qib tom qab hloov pauv los ntawm osmotic tone, tshwj xeeb tshaj yog nyob rau hauv qhov chaw ntawm lub nephron, qhov loj ntawm kev hloov pauv ntawm lub cev tonicity yeej [22 ]. Qhov tseeb, MR cov ntaub ntawv teev npe txo qis hauv qab hypertonicity tom qab nrhiav neeg ua haujlwm ntawm RNA Binding Protein (RBP) Tis11b (tetradecanoyl phorbol acetate inducible sequence 11b), uas lub cev cuam tshuam nrog 30 - cheeb tsam tsis tau txhais ({{11}UTR) ntawm MR ranscript , yog li modulating nws mRNA turnover nyob rau hauv teb rau osmotic kev nyuaj siab [23]. Ntawm qhov tsis sib xws, MR transcript qib nce hauv hypotonicity ua tsaug rau kev nrhiav neeg ua haujlwm ntawm Human antigen R (HuR), lwm RBP, uas cuam tshuam nrog MR 30 -UTR hauv cytoplasm ntawm lub raum hlwb kom stabilize thiab nce MR qib, yog li kev hloov pauv. MR signaling [24]. Cov ntaub ntawv pov thawj tam sim no qhia txog lub luag haujlwm tseem ceeb ntawm microRNAs (miRNAs), ib chav kawm ntxiv ntawm cov kws tswj xyuas kev hloov pauv tom qab, hauv kev tswj hwm ntawm MR qhia hauv lub raum [25,26]. Tshaj li cov txheej txheem tswj hwm no, MR kev ua haujlwm thiab kev taw qhia kuj tau hloov kho los ntawm kev hloov pauv tom qab kev hloov pauv xws li ubiquitylation, SUMOylation, phosphorylation, thiab acetylation [13,27].

3. Glucocorticoid Signaling Pathway

3.1. Glucocorticoid Hormones thiab Hypothalamic-Pituitary-Adrenal Axis

Glucocorticoid cov tshuaj hormones (cortisol thiab corticosterone hauv cov nas) yog cov tshuaj hormones ntawm Hypothalamic-Pituitary-Adrenal (HPA) axis ntawm neuroendocrine system thiab yog tsim los ntawm adrenal Zona fasciculata (ZF). Raws li rau tag nrho cov tshuaj hormones steroid, cortisol synthesis pib los ntawm cov roj (cholesterol) thiab yog qhov tseem ceeb ntawm Star protein, uas ua rau muaj kev cuam tshuam sai ntawm cov cholesterol mus rau hauv mitochondria. Tom qab ntawd, mitochondrial enzyme, cytochrome P450scc, encoded los ntawm CYP11A1 noob cleaves cov roj cholesterol sidechain rau pregnenolone. Pregnenolone passively diffuses rau hauv endoplasmic reticulum thiab hloov mus rau progesterone los ntawm 2–3 -hydroxysteroid dehydrogenase/∆5-∆4 isomerase (3 HSD2), uas yog encoded los ntawm HSD3B2 noob. Cov lus qhia tshwj xeeb ntawm P450c17 (encoded los ntawm CYP17A1 noob) catalyzes lub 17 -hydroxylation ntawm progesterone rau 17OH progesterone (17OHP). Tom qab ntawd, 17OHP tau hloov pauv mus rau 11-deoxycortisol tom qab ntawd mus rau cortisol los ntawm microsomal P450c21 thiab mitochondrial P450c11 (encoded los ntawm CYP11B1 noob), feem. Hauv cov nas, ZF tsis muaj P450c17 thiab progesterone yog 21- thiab 11 -hydroxylated los ua corticosterone, es tsis txhob cortisol, raws li qhov tseem ceeb ntawm glucocorticoid hauv cov hom no [2]. Glucocorticoid synthesis yog qhov sib txawv ntawm cov qog adrenal ua ntej thiab tom qab yug menyuam. Hauv cov neeg laus, glucocorticoid ntau lawm yog tswj hwm los ntawm kev ua haujlwm ntawm HPA axis. Ntau yam stimuli xws li kev ntxhov siab, kev mob, lossis lub circadian atherosclerosis ua rau kev tso tawm ntawm Corticotropin-Releasing Hormone (CRH) los ntawm hypothalamus, uas txhawb nqa lub caj pas pituitary, tso tawm ACTH. ACTH ua rau MC2R hauv adrenal ZF kom ua rau corticosteroid synthesis los ntawm cov cholesterol. Nyob rau hauv lem, circulating glucocorticoids tawm tswv yim tswj cov nyhuv ntawm lub hypothalamus thiab ntawm lub pituitary inhibit qhov tso tawm ntawm CRH thiab ACTH, raws li [2]. Fetal adrenal qog muaj peev xwm ntawm steroidogenesis sai tom qab lawv tsim nyob ib ncig ntawm 7th GW. Nyob rau tib lub sijhawm, pituitary pib tsim ACTH. Kev tso tawm ntawm cortisol nce mus rau qhov siab kawg ntawm 8-9 GW; ces, nws txo mus txog 14 GW. Qhov no cyclic secretion ntawm glucocorticoids los ntawm fetal qog adrenal tsis nyob rau hauv kev tswj ntawm ACTH, zoo li hauv cov laus [28]. Qhov tseeb, qib ACTH tseem nyob tas li thaum lub sijhawm no thiab txhawb cov qog adrenal los tsim cov androgens. Qhov kev qhia ntawm 3 HSD2 uas nce siab ntawm 9 GW txo tom qab ntawd thoob plaws feem ntau ntawm peb lub hlis thib ob, ua rau txo qis hauv glucocorticoid synthesis. Ntawm 24 GW, kev qhia ntawm 3 HSD2 thiab kev tso tawm ntawm glucocorticoids rov pib dua. Cortisol surges nyob rau hauv lub lis piam ua ntej yug me nyuam thiab plays lub luag hauj lwm tseem ceeb hauv kev sib txawv thiab kev ua haujlwm ntawm ntau lub cev xws li lub ntsws [29]. Kev sib deev dimorphism hauv HPA axis kev ua ub no tau pom tias muaj nyob rau thaum yau. Hauv kev tshuaj ntsuam meta, basal HPA axis kev ua haujlwm tau pom zoo kom muaj ntau dua ntawm cov tub hluas ua ntej 8 xyoo, raws li kev ntsuas los ntawm salivary cortisol qib [30]. Tom qab 8 xyoo, cov qauv no zoo li thim rov qab, qhia txog kev hloov pauv ntawm kev sib deev tshwj xeeb ntawm cortisol metabolism nyob ib puag ncig kev laus [31] thiab muaj peev xwm ua tau ntawm kev ua neej nyob thaum ntxov [32]. Txawm li cas los xij, tsis muaj qhov sib txawv thaum yug los ntawm cov ntxhais thiab cov tub txog qib basal plasma cortisol [33]. Cortisol metabolism nyob ntawm kev ua haujlwm ntawm daim siab A-ring reductases (5- thiab 5- -reductase) thiab 11beta-hydroxysteroid dehydrogenase (11 HSD) isoenzymes. 11 HSD1 enzyme yog tsuas yog qhia nyob rau hauv daim siab thiab adipose ntaub so ntswg, thiab nws regenerates cortisol los ntawm nws inactive compound cortisone. 11 HSD2 enzyme catalyzes cov tshuaj tiv thaiv rov qab hauv lub raum epithelial hlwb (saib Tshooj 4.2). Hauv cov neeg laus, cov poj niam tau pom tias muaj qhov tso zis qis qis ntawm cortisol metabolites piv rau cov txiv neej, uas tau raug ntaus nqi los txo qis A-ring [34]. Qhov sib txawv ntawm kev sib deev hauv cortisol metabolism pib nyob ib ncig ntawm lub hnub nyoog laus, thaum muaj hnub nyoog 10-11 xyoo [31,35], thiab nws tau khaws cia rau hauv cov neeg laus hais txog kev tswj hwm cov txheej txheem ib feem ntawm kev ywj pheej ntawm gonadal steroids [36].

3.2. Glucocorticoid Receptor

3.2.1. Gene, Transcripts, thiab Protein Variants

GR yog tus tsim cov tswv cuab ntawm cov neeg txais xov tooj cua superfamily. Qhov kev hloov pauv no, zoo ib yam li MR, muaj 4 lub ntsiab tseem ceeb, NTD, DBD, LBD, thiab Hinge Region (HR) ntawm DBD thiab LBD [37]. Nws yog encoded los ntawm NR3C1 noob nyob rau ntawm chromosome 5 (5q31) hauv tib neeg. NR3C1 noob muaj tsawg kawg yog 10 exons [38]. Lwm qhov kev sib txuas ntawm exon 9 ua rau ob qhov sib txawv loj ntawm cov protein, GR, uas yog cov sib txawv ntawm ligand-dependent variant, thiab GR, uas yog ligand-independent variant exerting dominant-negative effect [39]. GR yog 777 amino acids ntev protein [40]. Cov GR protein muaj cov chaw rau kev hloov pauv tom qab kev txhais lus, xws li SUMOylation lossis phosphorylation, uas cuam tshuam rau nws cov peev txheej transactivation. 3.2.2. Mechanisms of Regulation of GR Expression and Activity GR yog tam sim no nyob rau hauv yuav luag tag nrho cov hlwb, tab sis rhiab heev rau glucocorticoids yog cov ntaub so ntswg-nyob thiab ib nrab kho los ntawm kev tswj ntawm GR qhia. Cov kev cai no yog kho kom haum xeeb nyob rau theem transcriptional los ntawm ob lub ntsiab mechanisms: lwm splicing ntawm lub 1st exon thiab variability nyob rau hauv qhov ntev ntawm N-terminal domain. Thawj thiab tsis tau txhais exon muaj cuaj qhov chaw pub dawb zoo khaws cia ntawm cov tsiaj, sib xws rau cov chaw tau txais splice ntawm exon 2 [41] txhua tus nyob rau hauv kev tswj hwm ntawm ib tus neeg txhawb nqa tshwj xeeb. Qhov kev hloov pauv no ua rau lwm qhov mRNA isoforms, uas txawv hauv lawv thaj tsam 50 -UTR. Kev qhia ntawm mRNA isoforms yog cov ntaub so ntswg tshwj xeeb. Lub 2nd exon muaj yim sib txawv pib codons, encoding rau yim qhov sib txawv ntawm GR (GR-A, GR-B, GR-C1, GR-C2, GR-C3, GR-D1, GR-D2, thiab GR-D3) . Cov kev sib txawv no muaj kev sib npaug sib luag rau cov ligand tab sis txawv ntawm cov peev txheej transactivation thiab cov hom phiaj, tsuas yog<10% of="" them="" common="" to="" all="" variants="" [42].="" 4.="" mechanism="" of="" corticosteroids="" action="" in="" renal="" principal="" cells="" 4.1.="" subcellular="" distribution="" in="" renal="" principal="" cells,="" corticosteroid="" hormones="" enter="" by="" passive="" diffusion="" and="" bind="" their="" respective="" receptor:="" aldosterone="" to="" the="" mr="" and="" cortisol="" (or="" corticosterone)="" to="" the="" gr.="" in="" the="" absence="" of="" ligands,="" corticosteroid="" receptors="" are="" associated="" with="" chaperone="" proteins="" [43–46],="" which="" protect="" receptors="" from="" degradation="" and="" maintain="" a="" conformation="" suitable="" for="" binding="" to="" ligands.="" thereafter,="" the="" binding="" of="" either="" ligand="" induces="" the="" dissociation="" of="" these="" chaperone="" proteins="" and="" conformational="" changes="" of="" mr="" and="" gr.="" 4.2.="" mineralocorticoid="" selectivity="" given="" the="" homology="" existing="" between="" the="" structure="" of="" aldosterone="" and="" cortisol/="" corticosterone,="" the="" high="" homology="" between="" mr="" and="" gr="" (their="" dbd="" and="" lbd="" have="" 94%="" and="" 57%="" homology,="" respectively="" [47]),="" and="" similar="" affinity="" of="" both="" receptors="" for="" glucocorticoid="" hormones,="" mr="" would="" be="" expected="" to="" be="" permanently="" occupied="" by="" glucocorticoid="">

Tseeb tiag, cortisol plasma concentrations nce mus txog 100 mus rau 1000 npaug siab dua li ntawm aldosterone hauv cov tsiaj. Txawm li cas los xij, MR kev ua haujlwm tsis raug cai los ntawm glucocorticoid cov tshuaj hormones yog txwv nyob rau hauv lub raum tus thawj tswj hwm thiab lwm cov hlwb epithelial los ntawm kev ua ntawm 11 HSD2 [48-50]. Cov enzyme no oxidizes cawv muaj nuj nqi nqa los ntawm carbon 11 ntawm cov tshuaj hormones glucocorticoid rau hauv ketone muaj nuj nqi, yog li tsim 11 dehydrogenated derivatives (cortisone nyob rau hauv tib neeg thiab 11-dehydrocorticosterone nyob rau hauv nas) uas muaj tsawg los yog tsis muaj affinity rau MR, los yog txawm rau TSI [48]. Yog li, 11 HSD2 tso cai rau aldosterone los ua kev xaiv rau MR hauv cov hlwb epithelial kom nws cov teebmeem lom ntawm sodium reabsorption (Daim duab 1). Tsis tas li ntawd, MR kuj tseem tuaj yeem cais tawm ntawm aldosterone thiab cortisol vim tias qhov sib txawv ntawm cov tshuaj glucocorticoids sai dua rau aldosterone. Kev sib cuam tshuam ntawm NTD thiab LBD tshwm sim vim tias aldosterone-MR complex siv cov qauv kev sib txawv ntawm qhov sib txawv ntawm glucocorticoid-MR complex [51]. Thaum kawg, nws tau pom tias qhov xwm txheej ntawm ligand kuj tseem tuaj yeem hloov kho lub voj voog ntawm kev sib cuam tshuam ntawm ligand-receptor complex nrog DNA teb cov ntsiab lus [52].

4.3. Txhawb Kev Sib Txuas thiab Kev Ua Haujlwm ntawm Coregulators

Ib zaug nyob rau hauv lub nucleus, lub aldosterone-MR complex khi feem ntau yog homodimers rau Mineralocorticoid Response Elements (MREs) nyob rau hauv cov cheeb tsam tswj hwm ntawm MR hom phiaj noob [53]. Tom qab ntawd, MR cuam tshuam, nyob rau hauv ib lub voj voog, ntu ntu, thiab / lossis kev sib txuas ua ke [52], nrog cov kev hloov pauv hloov pauv [54] thiab qee qhov basal transcription yam lossis cov khoom siv ntawm lub tshuab los txhim kho kev ua kom transcriptional thiab pab txhawb chromatin remodeling nrog histone acetylation / methylation [53]. Interestingly, Le Billan et al., siv HK GFP-MR hlwb, tib neeg lub raum kab ntawm tes uas tsis muaj 11 HSD2 los txiav txim qhov kev koom tes ntawm MR / GR thiab aldosterone / cortisol hauv lub raum corticosteroid signaling. Cov kws sau ntawv no tau muab pov thawj tias MR thiab GR muaj kev cuam tshuam thiab sib cuam tshuam ntawm tib lub hom phiaj txhawb nqa ntawm Lub Sijhawm circadian protein 1 (PER1) gene, hauv ib qho tshwj xeeb thiab sib txawv ntawm kev kos npe, los ntawm kev khi ua homo- lossis heterodimers [52]. Hauv cov nucleus, GR kuj tuaj yeem khi cov kab ke tshwj xeeb hu ua Glucocorticoid Response Elements (GREs). Hauv txhua hom cell, GR khi sib txawv GREs. Kev khi rau GRE qhib kev nrhiav neeg ua haujlwm ntawm chromatin-remodeling complexes thiab coregulators, xws li steroid receptor coactivator-1 (SRC-1), uas tso cai rau kev tsim cov kev pib transcription complex. Tsis zoo GRE (nGRE) kuj tau tshaj tawm, uas yog lub luag haujlwm rau kev cuam tshuam ntawm cov hom phiaj. Kev khi rau nGRE tiv thaiv dimerization thiab tso cai rau kev nrhiav neeg ua haujlwm ntawm corepressors, xws li NCoR lossis SMRT [55]. GR kuj tseem tuaj yeem kho kom haum rau kev hloov pauv ntawm cov hom phiaj los ntawm kev sib txuas raws li tau piav qhia rau MR [53] los ntawm kev cuam tshuam nrog lwm yam kev hloov pauv raws li NF-κB lossis AP-1 yam tsis muaj kev khi ncaj qha rau DNA [56].

4.4. MR thiab GR Target Genes

Hauv aldosterone-rhiab heev nephron, MR koom nrog kev tswj hwm ntawm ntsev sib npaug los ntawm kev txhawb nqa kev qhia ntawm ionic transporters xws li Epithelial Na ntxiv Channel (ENaC) [57] thiab Na plus, K ntxiv -ATPase twj tso kua mis [58]. Cov neeg thauj khoom no ua rau cov transepithelial reabsorption ntawm sodium los ntawm lumen mus rau interstitium. Aldosterone kuj txhawb nqa, los ntawm kev ua kom MR, kev qhia ntxov ntawm Serum thiab glucocorticoid-regulated kinase 1 (SGK1) [59], uas phosphorylates ubiquitin ligase Nedd 4-2, uas nyob rau hauv lem tswj cov retrieval ntawm ENaC los ntawm apical membrane. . Lwm cov noob caj noob ces kuj tau txheeb xyuas hauv lub raum, suav nrog serine / threonine kinase Tsis muaj lysine K kinase (KS-WNK1) [60], N-myc Down-Regulated Gene 2 (NDRG2) [61], Glucocorticoid- Induced Leucine Zipper protein (GILZ) [62], uas tseem ua lub luag haujlwm tseem ceeb thaum lub sijhawm ntxov ntawm cov lus teb aldosterone [13] (Daim duab 1). Tsis ntev los no, aldosterone tau pom los tswj lub suab ntawm lub raum sodium reabsorption los ntawm kev txhawb nqa qhov kev qhia ntxov ntawm PER1 noob [63]. Nws kuj tau tshaj tawm tias MR tuaj yeem cuam tshuam ncaj qha rau kev lees paub motifs rau lwm yam kev hloov pauv (FOX, EGR1, AP1, PAX5) los ntawm tethering mechanisms, raws li tau tshaj tawm rau GR, yog li ua rau kev hloov pauv ntawm lub hom phiaj gene qhia [53]. Hauv cov neeg laus lub raum, raws li 11 HSD2 qhia tau siab, tsis muaj kev cuam tshuam loj ntawm GR signaling yuav tsum nyob rau hauv cov xwm txheej basal [64].

Qhov tseem ceeb, peb pab pawg tau tsis ntev los no tau txheeb xyuas qhov tshwj xeeb ntawm lub cev lub cev thaum lub raum kev loj hlob, thaum lub sij hawm qhov kev taw qhia MR no tsis muaj txiaj ntsig vim yog kev cai qis ntawm MR qhia [65]. Yog li ntawd, vim hais tias lub raum 11 HSD2 tsis qhia thaum lub sij hawm perinatal tshwj xeeb, GR signaling yuav tsum ua hauj lwm nyob rau hauv lub raum lub hauv paus tseem ceeb hlwb, nrog rau cov plasma cortisol qib kuaj pom nyob rau hauv physiological nqi nyob rau hauv cov me nyuam mos zoo ib yam li cov neeg laus theem [66]. Hauv cov ntsiab lus no, GR zoo li yuav ua rau lub raum lub hom phiaj cov noob caj noob ces thiab cov hom phiaj hom phiaj nrog cov MR suav nrog SGK1 lossis GILZ. GR thiab MR cov hom phiaj tshwj xeeb hauv lub raum lub raum lub hauv paus tseem ceeb tau sau tseg hauv Table 1.

Daim duab 1. Mineralocorticoid thiab glucocorticoid signaling nyob rau hauv lub raum lub hauv paus ntsiab lus. Corticosteroid cov tshuaj hormones nkag los ntawm kev sib kis tsis zoo thiab khi lawv cov receptor: aldosterone rau MR thiab cortisol / corticosterone rau GR. Thaum tsis muaj ligands, corticosteroid receptors yog txuam nrog chaperone proteins. Tom qab ntawd, kev sib txuas ntawm ob lub ligand induces dissociation ntawm cov chaperone proteins thiab conformational hloov ntawm MR thiab GR. Hauv cov nucleus, aldosterone / MRcomplex khi feem ntau ua homodimers rau Mineralocorticoid Response Elements (MREs). Tom qab ntawd, MRinteracts, nyob rau hauv ib tug cyclic, sequential, thiab / los yog combinatorial yam, nrog transcriptional coregulators thiab ib co basal transcription yam tseem ceeb los yog cov khoom ntawm lub tshuab los txhim kho cov transcription ntawm lub hom phiaj noob, nrog rau cov Epithelial Na ntxiv Channel (ENaC), lub Na plus. , K ntxiv -ATPase twj tso kua mis. Aldosterone kuj tseem txhawb nqa kev qhia ntxov ntawm Serum thiab glucocorticoid-regulated kinase 1 (SGK1), serine / threonine kinase Tsis muaj lysine K kinase (KS-WNK1), N-myc Down-Regulated Gene 2 (NDRG2), thiab glucocorticoid. -Induced Leucine Zipper protein (GILZ). Tsis ntev los no, aldosterone tau pom los txhawb kev qhia ntxov ntawm PER1 noob, uas yog nyob rau hauv tsev neeg circadian moos gene. Nws kuj tau tshaj tawm tias MR tuaj yeem khi ncaj qha rau kev lees paub motifs rau lwm yam kev hloov pauv (FOX, EGR1, AP1, PAX5) los ntawm tethering mechanisms. Hauv lub raum lub raum tseem ceeb, 11 HSD2 hloov glucorticoid cov tshuaj hormones rau hauv cortisone lossis 11-dehydrocorticosterone uas muaj tsawg lossis tsis muaj kev sib raug zoo rau MR, lossis txawm rau GR. Yog li, 11 HSD2 tso cai rau aldosterone los ua kev xaiv rau MR tshwj xeeb rau nws cov teebmeem lom ntawm sodium reabsorption. Tsis tas li ntawd, GR tsis yog los yog tsis muaj zog activated.MR: Mineralocorticoid Receptor; GR: Glucocorticoid Receptor; MRE: Mineralocorticoid ResponseElement; GILZ: Glucocorticoid-induced leucine zipper; EnaC: Epithelial Na ntxiv Channel; Sgk 1: Serum thiab Glucocorticoid-Regulated kinase 1; KS-WNK1: Tsis muaj lysine K kinase; NDRG2: N-mycDown-Regulated Gene 2; PER 1: moos noob sij hawm 1; TM: Transcriptional Machinery.

5. Kev sib deev Dimorphism ntawm Corticosteroid Signaling Ib sab ntawm lub raum

Ntau qhov kev tshawb fawb tau muab pov thawj rau kev qhia txog poj niam txiv neej sib txawv thiab ua kom MR thiab GR. Piv txwv li, rov qab kho cov tshuaj antenatal glucocorticoid tau qhia rau kev ua haujlwm HPA hauv kev sib deev tshwj xeeb, thiab cov kev hloov no tau cuam tshuam nrog kev hloov kho ntawm MR thiab GR qhia hauv cov neeg laus lub hlwb thiab pituitary [68]. Thaum lub sij hawm txoj kev loj hlob, tib neeg sau ntawv tau pom tsawg GR mRNA nyob rau hauv lub paraventricular nucleus, txo MR mRNA thiab MR protein nyob rau hauv lub hippocampus, thiab nce GR mRNA thiab GR proteins nyob rau hauv lub hippocampus. Hauv cov npua guinea, leej niam tswj hwm glucocorticoids txo qis hauv plasma ACTH thiab cortisol ntau thiab cuam tshuam rau hippocampal MR protein qhia, thiab cov nyhuv no loj tshaj rau cov txiv neej. Qhov sib txawv ntawm poj niam txiv neej nyob rau hauv tus qauv ntawm GR thiab MR qhia thaum lub sij hawm txoj kev loj hlob yuav qhia tau hais tias txawv qhov rais ntawm qhov tsis zoo rau prenatal glucocorticoid raug nyob rau hauv fetal lub neej [69]. Cov corticosteroid receptors no kuj tau pom tias ua lub luag haujlwm tseem ceeb hauv kev hloov pauv ntawm kev ntxhov siab hauv lub hlwb nas. Tseeb tiag, kev koom tes ntawm poj niam txiv neej thiab ntawm lub cellular ib puag ncig ntawm qee qhov chaw hauv hlwb rau kev qhia ntawm MR thiab GR tau tshaj tawm tom qab kev txwv tsis pub muaj kev ntxhov siab [70]. Tsis tas li ntawd, tib pab pawg tau pom tias cov poj niam nas tau nthuav tawm nrog cov txheej txheem sib txawv ntawm kev tswj hwm GR / MR piv hauv hippocampus thaum muaj kev ntxhov siab, thaum tus poj niam hypothalamus muaj ntau dua li cov txiv neej hloov corticosteroid receptor qhia hauv kev teb rau kev tswj hwm kev ntxhov siab. Ob peb lwm cov kev tshawb fawb kuj tau qhia txog qhov sib txawv ntawm poj niam txiv neej hauv MR qhia thiab ua kom lub siab [71–73]. Ib yam li ntawd, nws tau pom tias glucocorticoids siv lawv cov kev ua, tshwj xeeb tshaj yog kev tiv thaiv kab mob, hauv kev sib deev dimorphic [74,75]. Tsis tas li ntawd, estrogen tuaj yeem tiv thaiv GR-induction ntawm GILZ gene [76]. Txawm hais tias cov txheej txheem tswj hwm cuam tshuam nrog MR thiab GR kev qhia lossis lawv cov lus qhia, tuaj yeem ua rau muaj qhov tshwm sim ntawm kev sib deev dimorphism tseem yuav tau tshawb nrhiav. Thaum kawg, rau qhov zoo tshaj plaws ntawm peb txoj kev paub, tsuas yog ib txoj kev tshawb fawb tau qhia txog kev sib deev dimorphism rau corticosteroid receptors qhia hauv lub raum [77].

6. Qhov txawv ntawm poj niam txiv neej nyob rau hauv lub raum kev loj hlob thiab Organogenesis

Lub raum organogenesis yog cov txheej txheem nyuaj uas muaj peb txoj kev ua tiav, uas tsuas yog qhov kawg, metanephros, yuav muab lub raum meej [78]. Cov metanephros tsim los ntawm caudal nephrotomes pib los ntawm 5th GW, thiab nws kev loj hlob txuas ntxiv mus txog rau thaum xaus ntawm thawj xyoo ntawm lub neej postnatal hauv tib neeg [65], nrog rau kev loj hlob ntawm cov nephrons thiab ntawm qhov sib txawv ntawm cov ducts sau [79] ]. Lub raum ontogeny pib los ntawm kev sib cuam tshuam ntawm mesenchymal hlwb ntawm metanephros, uas yuav muab lub neej yav tom ntej nephrogenic qauv, thiab lub ureteral bud, ib tug epithelial qauv tsim los ntawm Wolffian duct, los ntawm lub raum sau system yuav tsim los ntawm successive dichotomies, raws li zoo raws li Classical branching morphogenesis [80]. Txhua ceg ntawm lub ureteral bud yog capped los ntawm metanephric hlwb, uas yog progenitor qia hlwb uas muaj peev xwm sib txawv rau txhua hom cell uas tsim cov glomeruli thiab nephrons [81]. Cov txheej txheem kev sib txawv no muaj peev xwm ua tau ua tsaug rau kev sib tham ntawm ob lub qauv thiab kev qhia ua tiav ntawm txoj kev sib txawv ntawm kev taw qhia [82,83], qee qhov kev tswj hwm epigenetically [84] thiab yog li muaj feem cuam tshuam los ntawm cov xwm txheej tsis zoo tshwm sim thaum cev xeeb tub. Tshwj xeeb, Ang II, ua yeeb yam ntawm AT1R, kho qhov kev loj hlob thiab kev loj hlob ntawm lub raum tubules thiab branching morphogenesis [85]. Hauv qhov sib piv, AT2 Receptor (AT2R) nyob rau hauv lub raum fetal muaj kev tiv thaiv kev loj hlob hauv cov hlwb adrenomedullary interstitial thiab ua rau kho apoptosis [86]. Tag nrho cov txheej txheem no yog qhov tseem ceeb hauv kev txiav txim siab tus naj npawb kawg ntawm nephrons ib lub raum, uas ncaj qha cuam tshuam nrog lub raum ua haujlwm hauv cov neeg laus. Nephrogenesis yog qhov tseem ceeb antenatal [87], nruab nrab ntawm 5th thiab 36th GW, tab sis tshwj xeeb tshaj yog nyob nruab nrab ntawm 17th thiab 32nd GW, ua rau tag nrho cov nephrons hauv tib neeg ntawm 300, 000 thiab 1.1 lab [88]. Los ntawm cov kev tshawb fawb tau ua los ntawm kev kuaj mob los yog pub rau lub raum, nws paub tias muaj kev sib deev dimorphism hauv lub raum ntsuas hauv cov neeg laus, ob qho tib si hauv qhov tseem ceeb thiab cov txiaj ntsig txheeb ze ntawm thaj tsam ntawm lub cev, nrog cov txiaj ntsig ntau dua hauv cov txiv neej [89,90 ]. Qhov no txhais tau hais tias tus naj npawb ntawm tag nrho cov nephrons tuaj yeem siab dua rau cov txiv neej dua li poj niam, txawm tias qhov no tsis tau ua pov thawj hauv tib neeg hom. Interestingly, qhov kev sib deev dimorphism no tshwm sim thaum ntxov thaum lub sij hawm nephrogenesis, vim qhov sib txawv ntawm lub raum ntim tau pom nyob rau hauv ultrasound ntsuas nyob rau hauv lub fetus thaum lub sij hawm peb lub hlis twg ntawm cev xeeb tub, nrog rau cov me nyuam mos txog li 4 xyoo ntawm lub hnub nyoog [91-93]. Ntawm qhov tod tes, tsis muaj kev sib deev dimorphism tau pom nyob rau hauv cov nqe lus ntawm nephron suav nyob rau hauv lub sij hawm neonatal [94], tab sis cov ntaub ntawv no tau kawm tsis tshua muaj, ntawm pawg me me. Lub raum ontogeny nyob rau hauv tus nas kuj zoo ib yam li cov tib neeg hom, nrog rau succession ntawm peb cov qauv, pronephros los ntawm 8th hnub ntawm gestation (E8), mesonephros los ntawm E9, thiab metanephros los ntawm E11. Qhov sib txawv tseem ceeb yog nyob rau hauv hom murine, nephrogenesis txuas ntxiv tom qab yug menyuam mus txog thaum kawg ntawm thawj lub lim tiam ntawm lub neej. Ntxiv mus, kev sib deev dimorphism nyob rau hauv lub raum ntim tsis muaj nyob rau hauv lub cev xeeb tub lub sij hawm nyob rau hauv nas [95], uas tej zaum yuav muaj feem xyuam rau qhov ncua sij hawm ntawm qhov tau txais cov nephrons tshiab. Txawm li cas los xij, nws zoo nkaus li zoo, nrog rau kev hloov pauv ntawm cov txheej txheem histological, pib txij li 50 hnub ntawm lub neej, piv txwv li, tom qab pib ua tiav ntawm cov nas [95]. Kev cuam tshuam ncaj qha ntawm testosterone ntawm lub raum ntim tau pom nyob rau hauv nas qauv ntawm cov tub ntxhais hluas castrated txiv neej thib ob raug rau testosterone lossis tsheb [96]. Cov nyhuv trophic ntawm testosterone ntawm kev loj hlob ntawm lub cev, nrog rau lub raum, kuj tau pom nyob rau hauv tib neeg kev tshawb fawb soj ntsuam [97]. Yog li, kev sib deev dimorphism nyob rau hauv lub raum organogenesis thaum ntxov li peb lub hlis twg hauv tib neeg hom yuav muaj feem xyuam rau testosterone secretion los ntawm txiv neej fetuses hauv utero [98]. Cov kev tshawb fawb ntawm kev ua ntej yug menyuam rau testosterone tau pom tias lub raum tsim muaj qhov cuam tshuam rau testosterone [99], tab sis nws qhov cuam tshuam rau lub raum kev loj hlob nyob rau hauv lub cev xeeb tub hauv lub fetus, nrog rau kev sib cuam tshuam ntawm lub cev ntawm androgen signaling pathways thiab lwm yam kev cuam tshuam hauv lub raum. nephrogenesis, tseem yuav ua kom pom ntxiv.

7. Qhov tshwj xeeb ntawm Mineralocorticoid thiab Glucocorticoid Cov Teeb Meem Thaum Lub Raum Kev Loj Hlob

Lub raum yog ib qho tseem ceeb rau cov ntaub so ntswg lub hom phiaj ntawm corticosteroid qhia txoj hauv kev thiab ua lub luag haujlwm tseem ceeb hauv lub sijhawm yug menyuam. Tib neeg neonates tam sim no nrog kev tsis taus sodium thiab dej reabsorption thaum thawj lub hlis ntawm lub neej, uas cuam tshuam rau ib feem ntawm tubular tsis kam rau aldosterone [65] nrog rau cov ntshav plasma aldosterone siab nyob rau hauv thawj lub hlis ntawm lub neej nrog kev loj hlob normalization rau cov neeg laus qhov tseem ceeb [10]. Peb pab pawg tau pom tias qhov kev ncua ntev thiab ib nrab tsis kam rau aldosterone hauv cov menyuam mos noj qab haus huv tag nrho yog cuam tshuam rau cov tubular MR qhia thaum yug me nyuam, thaum MR tau hais tawm nyob rau hauv lub raum fetal ntawm 14th thiab 24th GW [65]. Perinatal down-regulation ntawm lub raum MR qhia tsis yog tshwj xeeb rau lub raum, raws li nws kuj muaj nyob rau hauv lwm yam mineralocorticoid lub hom phiaj cov ntaub so ntswg xws li lub plawv thiab lub hlwb ntawm variance nrog lub ntsws uas MR qhia tau khaws cia thaum yug los [100]. Qhov zoo siab, qhov kev qhia ntawm lub cev thiab cov ntaub so ntswg tshwj xeeb ntawm cov cim qhia mineralocorticoid pom ob qho tib si hauv nas thiab tib neeg, ua kom pom tias muaj kev txuag zoo uas yuav muaj lub luag haujlwm tseem ceeb hauv kev hloov ntawm cov dej hauv lub tsev menyuam mus rau lub neej hauv av [65]. Qhov kev hloov pauv no hauv MR qhia tsis cuam tshuam txog qhov siab aldosterone secretion thaum yug los, txij li thaum aldosterone synthase, cov nas uas muaj kab mob tshwm sim nrog tib qho kev cai ntawm lub raum MR qhia [101]. Txawm li cas los xij, tag nrho lwm tus neeg ua si ntawm txoj kev qhia pom mineralocorticoid ua raws li cov qauv biphasic ntawm kev qhia, xws li 11 HSD2 lossis ENaC [65]. Qhov zoo siab, txoj cai qis ntawm 11 HSD2 nyob rau hauv lub raum tsis pom nyob rau hauv cov placenta, qhov uas nws qhia tau siab thaum lub sij hawm cev xeeb tub los tiv thaiv tus me nyuam hauv plab los ntawm impregnation ntau dhau los ntawm leej niam glucocorticoids [66]. Txawm hais tias txoj kev qhia txog mineralocorticoid yog qis-tswj thaum lub sij hawm perinatal, qhov kev qhia ntawm GR tau kuaj pom nyob rau hauv lub raum tubular hlwb, thiab cov qib plasma cortisol pom nyob rau hauv lub cev muaj nuj nqis hauv cov me nyuam mos [66]. Muab hais tias 11 HSD2 tsis raug kuaj pom, lub raum glucocorticoid txoj hauv kev tau qhib thiab tsis tuaj yeem tswj tau, yog li txhawb lub tswv yim ntawm kev sib npaug ntawm mineralocorticoid thiab glucocorticoid signaling pathways thaum lub sijhawm tshwj xeeb ntawm kev txhim kho (Daim duab 2). Raws li kev txheeb cais, cov kab mob mineralocorticoid thiab glucocorticoid cov cim qhia tau nruj nruj thaum lub sijhawm cev xeeb tub thiab nthuav tawm lub sijhawm ua haujlwm siab thiab qis, nyob ntawm theem kev loj hlob. Mineralocorticoid signaling ib ntus txo qis nyob ib puag ncig lub sijhawm perinatal thaum lub sijhawm glucocorticoid tso tawm qis ntawm 14 thiab 24 GW thiab nce exponentially ua ntej yug. Cyclic impregnation hauv mineralocorticoids thiab glucocorticoids zoo li yog ib feem ntawm cov txheej txheem hloov mus rau lub neej extrauterine.

8. Kev sib deev Dimorphism nyob rau hauv qhov sib npaug ntawm lub raum Mineralocorticoid thiab Glucocorticoid Signaling

Ntau cov txheej txheem uas tsis yog kev yug menyuam muaj kev sib deev dimorphic kev cai. Ntshav siab yog ib qho zoo tshaj plaws, nrog rau qhov sib txawv ntawm kwv yees li 15 mmHg ntawm systolic ntshav siab hauv cov txiv neej thiab cov poj niam ua ntej cev xeeb tub [102]. Qhov siab dua systolic ntshav siab nyob rau hauv cov txiv neej yog khaws cia nyob rau hauv tag nrho cov tsiaj, qhia kom zoo-preserved mechanisms [103]. Hauv cov neeg laus, qhov cuam tshuam ncaj qha ntawm testosterone ntawm cov ntshav siab tau pom nyob rau hauv ntau yam tsiaj qauv nrog castration thiab testosterone hloov cov kev sim [104], thaum ovariectomy tsis muaj kev cuam tshuam rau ntshav siab hauv cov poj niam nas [105]. Kev sib deev steroids paub tias cuam tshuam rau kev ua haujlwm ntawm RAS hauv cov neeg laus: testosterone txhawb kev txiav txim ntawm Ang II ntawm AT1R, thaum cov tshuaj estrogen txo qhov AT1R / AT2R piv inducing sib txawv receptivity rau Ang II [103]. Peb pab pawg tau soj ntsuam kev sib deev thiab kev tswj hwm lub cev tshwj xeeb ntawm cov hom phiaj ntawm corticosteroid signaling txoj hauv kev hauv cov nas laus, nrog rau kev qhia ntau dua ntawm lub raum 11 HSD2 hauv cov poj niam nas, txhawb kev xaiv ntawm aldosterone rau nws cov receptor [77]. Qhov kev ua kom muaj zog ntxiv ntawm txoj hauv kev mineralocorticoid hauv cov poj niam tsis ua kom ntshav siab tab sis tuaj yeem ua rau muaj kev tswj hwm zoo ntawm cov tshuaj potassium excretion los ntawm distal tubules, uas yog ib qho kev hloov kho zoo rau niam-fetal homeostasis thaum cev xeeb tub [106]. Ntawm kev txaus siab, Zheng et al. tau tshaj tawm tias cov teebmeem ntawm aldosterone ntawm plasma K ntxiv tau txhim kho cov poj niam piv nrog cov txiv neej. Cov kws sau ntawv no tau ua pov thawj tias ob qho tib si Estrogen Receptors (ER thiab ER) tau pab txhawb rau cov tshuaj estrogen-vim txo qis hauv cov ntshav plasma K ntxiv thiab AT1R khi hauv ovariectomized poj niam nas [107]. Cov ntaub ntawv nyob rau hauv lub fetus loj hlob thiab cov me nyuam mos yog tsawg dua. Txawm hais tias tsis muaj qhov sib txawv ntawm CYP11B1 thiab CYP11B2 gene qhia lossis steroid concentrations ntawm aldosterone thiab cortisol / corticosterone tau tshaj tawm ntawm cov txiv neej thiab poj niam fetuses thaum loj hlob lossis thaum yug los, kev sib deev tshwj xeeb MR thiab 11 HSD2 qhia tau pom [77]. Peb pab pawg tau tshaj tawm txog kev sib deev dimorphism nyob rau hauv lub raum qhia ntawm MR thiab nws lub hom phiaj genes thaum lub sij hawm perinatal lub sij hawm, nrog ib tug ncov nyob rau hauv MR, GR, thiab mRNA qhia ntawm lub hom phiaj noob ntawm 17.5 hnub ntawm cev xeeb tub nyob rau hauv poj niam nas tab sis tsis nyob rau hauv cov txiv neej. Cov ntaub ntawv no zoo ib yam nrog kev kawm yav dhau los ntawm Codon li al., uas qhia txog kev ua haujlwm ntau dua ntawm 11 HSD2 hauv cov poj niam lub raum ntawm 15 hnub ntawm cev xeeb tub [108]. Nws zoo nkaus li tias hauv cov nas, qhov tsis sib xws ntawm MR thiab GR teeb liab txoj hauv kev hauv lub raum thaum lub sij hawm cev xeeb tub txhawb nqa cov teeb liab mineralocorticoid hauv cov poj niam. Qhov no tuaj yeem ua rau muaj txiaj ntsig zoo rau cov poj niam, tshwj xeeb tshaj yog nyob rau hauv lub ntsws, tso cai rau cov kua dej pulmonary thaum yug los los ntawm kev nthuav tawm ntawm EnaC [100]. Yog li, cov lus qhia pom nyob rau hauv cov txiv neej tuaj yeem txhais tau tias tsis zoo thiab cuam tshuam nrog kev mob hnyav dua los ntawm cov tub hluas thaum yug los, tshwj xeeb ntawm kev ua pa ua pa [101]. Tsis tas li ntawd, qhov no qhia tau hais tias txoj kev qhia txog glucocorticoid tuaj yeem ua tau zoo tshaj plaws hauv cov txiv neej, uas tej zaum yuav ua rau muaj kev txhim kho pathological tom qab raug kev ntxhov siab lossis glucocorticoids thaum cev xeeb tub.

9. Qhov tshwm sim hauv Pathphysiology

Muab qhov tsis txaus ntseeg ntawm glucocorticoid thiab mineralocorticoid teeb liab txoj hauv kev ntawm cov txiv neej thiab poj niam thaum lub sij hawm perinatal, nws muaj peev xwm hais tias qhov no yuav muaj kev cuam tshuam nyob rau hauv tej yam kab mob pathophysiological, nrog rau ntau dua rau cov txiv neej los tsim lub sij hawm ntev. Qhov "Kev Txhim Kho Keeb Kwm ntawm Kev Noj Qab Haus Huv thiab Kab Mob" qhov kev xav tau ua rau muaj kev txaus siab rau kev nkag siab txog cov xwm txheej tswj kev loj hlob ntawm fetal. Ntau yam kev ua tsis zoo ua ntej yug menyuam tuaj yeem koom nrog qhov pib ntawm cov kab mob hauv cov neeg laus nrog rau cov kab mob plawv thiab lub raum. Peb qhov kev xav yog tswj hwm los ntawm qhov muaj qhov sib txawv ntawm poj niam txiv neej nyob rau hauv qhov tshwm sim ntawm cov kab mob plawv, xws li ntshav siab thiab plawv tsis ua hauj lwm [109,110], uas tej zaum yuav yog qhov tshwm sim ntawm cov xwm txheej thaum ntxov perinatal [111].

Kev txwv kev loj hlob ntawm Fetal

Hauv tib neeg, ntau tus niam txiv glucocorticoids ua rau muaj kev txwv kev loj hlob ntawm fetus thiab muaj kev pheej hmoo siab ntawm ntshav siab tom qab lub neej [112,113]. Cov kev tshawb fawb (saib xyuas hauv [114]) siv cov qauv tsiaj (cov yaj, nas, thiab nas qauv) ntawm kev txwv kev loj hlob ntawm fetus xws li kev cuam tshuam rau leej niam glucocorticoid, kev txwv tsis pub niam txiv calorie lossis protein, thiab uteroplacental insufficiency, uas ua rau txo qis hauv 11 HSD2 placental. Kev qhia lossis ncaj qha fetal overexposure rau glucocorticoids [115] (tejzaum nws ua rau muaj kev ua haujlwm ntawm lub raum glucocorticoid signaling txoj hauv kev) tau txheeb xyuas qhov kev hloov pauv hauv lub raum kev loj hlob raws li qhov ua tau zoo. Interestingly, nyob rau hauv ntau yam tsiaj qauv ntawm txoj kev loj hlob programming, muaj kev sib deev dimorphism ntawm cov txiv neej thiab poj niam nyob rau hauv lub sij hawm ntawm qhov pib thiab mob hnyav tshwm sim. Qhov tseeb, tib qho kev thuam ntawm cev xeeb tub tsis tas yuav cuam tshuam rau txiv neej thiab poj niam zoo ib yam lossis rau tib qib [114]. Kev tsim cov nephron tsis tshua muaj txiaj ntsig tuaj yeem ua rau lub raum tsis ua haujlwm thiab tig mus, tuaj yeem ua rau muaj kab mob. Cov tsiaj ua qauv no tsim cov txheej txheem kub siab ib nrab vim yog hloov lub raum kev loj hlob, ua rau txo qis mus tas li ntawm cov xeeb ntxwv nephron endowment [116]. Hauv tib neeg, tus naj npawb ntawm nephrons muaj feem cuam tshuam nrog qhov hnyav thaum yug, nrog kwv yees nce ntawm kwv yees li 237,426 nephrons ib kilogram ntawm qhov hnyav ntxiv, tab sis nws tau cim ntau dua hauv cov txiv neej [117], uas yuav ua rau muaj kev sib txawv ntawm kev loj hlob ntawm kev kub siab ntawm txiv neej thiab poj niam. Qhov tseem ceeb, lub sij hawm ntawm nephrogenesis txawv ntawm cov tsiaj nrog tib neeg thiab yaj ua tiav nephron tsim ua ntej yug, thaum cov nas txuas ntxiv cov txheej txheem kev loj hlob tom qab yug me nyuam [116]. Qhov no txhais tau hais tias ob qho tib si ua ntej yug menyuam thiab tom qab yug menyuam tuaj yeem cuam tshuam rau nephron endowment hauv nas. Ib cag ntawm nephron endowment, kev hloov kho hauv kev qhia ntawm cov neeg sib txawv ntawm corticosteroid signaling pathways tau pom nyob rau hauv cov qauv no [114], uas tsis yog ib txwm nyob rau hauv kev koom tes nrog ib tug txo nyob rau hauv nephron tooj, yog li qhia tias lwm yam mechanisms cuam tshuam rau kev loj hlob programming. ntshav siab [118] AT1R thiab AT2R, uas tau qhia nyob rau hauv lub raum thaum ntxov thaum cev xeeb tub, muaj kev sib deev dimorphic hloov pauv hauv cov tsiaj qauv ntawm ntau dhau glucocorticoid fetal impregnation, feem ntau ua rau muaj kev nthuav qhia ntawm AT1R hauv cov txiv neej, nyob ntawm lub sijhawm ntawm kev ua phem ua ntej yug menyuam [114 ]. Cov txiaj ntsig ua ntej los ntawm peb pab pawg kuj qhia txog qhov txo qis hauv lub raum MR qhia nyob rau hauv perinatal glucocorticoid overexposure, nrog rau kev loj hlob ntawm kub siab thaum ntxov, tshwj xeeb tshaj yog nyob rau hauv cov txiv neej.

• Ua tsis taus pa

Kev yug ntxov ntxov yog txuam nrog kev pheej hmoo ntawm kev tuag thiab kev tuag [119]. Cov kev tshawb fawb hauv cov me nyuam mos ua ntej tau pom tias cov txiv neej muaj kev pheej hmoo siab dua ntawm cov kab mob xws li ua pa nyuaj siab, mob ntshav qab zib sepsis, bronchopulmonary dysplasia, thiab intraventricular hemorrhage tshaj cov poj niam [120] thiab cov txiaj ntsig ntev ntawm lub paj hlwb [121]. Tsis tas li ntawd, cov menyuam mos uas tsis muaj hnub nyoog dhau los muaj kev pheej hmoo siab dua los ntawm kev mob ntshav siab thaum ntxov hauv cov neeg laus lub neej [122], tshwj xeeb tshaj yog rau cov menyuam yaus uas tsis muaj hnub nyoog [123]. Cov kev sib deev sib txawv no tsis txuas rau qhov sib txawv hauv HPA axis muaj nuj nqi [33], tab sis lawv yuav muaj feem cuam tshuam rau kev nkag siab ntau dua rau kev tswj hwm ntawm antenatal corticosteroids hauv cov tub [124]. Nyob rau hauv tus qauv ntawm lipopolysaccharide-induced prematurity, tsim los ntawm peb pab pawg neeg, peb tau pom tias yav dhau los cov txiv neej ua ntej yug me nyuam muaj teeb meem kub siab nyob rau hauv neeg laus [125]. Qhov kev kub siab no cuam tshuam nrog kev hloov pauv thaum ntxov hauv kev qhia ntawm cov neeg sib txawv ntawm corticosteroid signaling pathway thaum lub sij hawm neonatal. Tseeb tiag, cov nas ntxov ntxov tau nthuav tawm lub cev muaj zog tshwj xeeb rau lub raum ua haujlwm ntawm kev qhia ntawm corticosteroid lub hom phiaj noob (ENac, Sgk1, thiab Girlz), uas sib piv nrog qhov txo qis hauv lub raum MR qhia. Qhov no qhia txog kev ua kom GR ua los ntawm glucocorticoids, uas tuaj yeem ua rau lub raum ua haujlwm lossis hloov pauv molecular, ua rau muaj ntshav siab hauv cov neeg laus. Txoj kev loj hlob ntawm kev mob ntshav siab tau piav qhia los ntawm Barker li al. [126], thiab cov txheej txheem hu ua feem ntau yog nephron endowment, ua rau kom them nyiaj hyperfiltration ntawm cov nephrons uas twb muaj lawm nrog glomerulosclerosis thiab proteinuria hauv cov neeg laus [127]. Ob peb txoj kev tshawb fawb tau pom tias muaj kev sib deev dimorphism nyob rau hauv no prematurity-induced nephron txo nyob rau hauv tib neeg, tab sis tsis muaj qhov sib txawv tau pom nyob rau hauv nas [128]. Hauv peb cov qauv, yav dhau los cov txiv neej nas ntxov ntxov tau tsim cov ntshav siab, ntawm nws tus kheej los ntawm nephron tus lej txo qis hauv cov neeg laus, qhia txog lwm cov txheej txheem pathophysiological koom nrog. Tsis tas li ntawd, ib txoj kev tshawb fawb hauv tib neeg tau pom tias qhov kev pab cuam ntawm kev kub siab tuaj yeem kis mus rau cov menyuam yaus ntawm cov menyuam mos uas tsis muaj hnub nyoog dhau los; Txawm li cas los xij, tus qauv me me tsis tso cai rau qhov txawv ntawm kev sib deev dimorphism [129]. Hauv peb tus qauv nas, peb tau txheeb xyuas kev sib kis ntawm cov ntshav siab dysregulation mus rau tiam tom ntej los ntawm cov menyuam yug tshiab, mus txog rau tiam thib peb. Interestingly, qhov no vascular anomaly tsuas yog kis tau nyob rau hauv cov txiv neej nyob rau hauv lub thib ob thiab thib peb tiam, uas yog txuam nrog ib tug tseem ceeb nce nyob rau hauv kev nthuav qhia ntawm corticosteroid lub hom phiaj gene Girlz thiab lub ntiaj teb no hypomethylation ntawm nws cov promotive [125]. Txoj kev tshawb no qhia tau hais tias ib tug predisposition rau arterial hypertension yuav tau epigenetically programmed nyob rau hauv cov txiv neej los ntawm cov xwm txheej tshwm sim nyob rau hauv lub perinatal lub sij hawm nyob rau hauv yav dhau los tiam los ntawm kev sib deev dimorphic adverse activation ntawm corticosteroid signaling txoj kev.

• Hloov mus

Pseudo-Hypoaldosteronism Thaum lub sij hawm ntxov tom qab yug me nyuam, lub raum mineralocorticoid thiab glucocorticoid tsis txaus kuj tuaj yeem cuam tshuam los ntawm cov kab mob tso zis. Tseeb tiag, nyob rau hauv cov ntaub ntawv ntawm lub urinary ib ntsuj av tau kab mob (pyelonephritis) nrog los yog tsis nyob rau hauv uropathy, ib ntus, tsis-physiological pseudo-hypoaldosteronism yuav tshwm sim [130]. Nws ua rau hyponatremia, hyperkalemia, metabolic acidosis, thiab lub cev qhuav dej hnyav nrog rau cov zis sodium loj, xav tau sodium ntxiv nyob rau theem mob hnyav. Transient pseudo-hypoaldosteronism muaj qhov tshwj xeeb tshwm sim feem ntau hauv cov menyuam mos hnub nyoog qis dua 3 lub hlis, nyob rau hauv kev cuam tshuam rau lub raum qis MR qhia ntawm lub sijhawm no ntawm kev loj hlob [65] thiab hauv 88 feem pua ​​​​ntawm cov txiv neej [130]. Cov kab mob pathophysiology tuaj yeem cuam tshuam nrog kev mob o (los ntawm kev ua kom muaj NF-κB yam) uas txuas ntxiv txo qis MR qhia thiab ua kom [131]. Raws li MR qhia tau qis dua hauv cov txiv neej thaum lub sijhawm perinatal [77], lawv tshwm sim ntau dua rau qhov poob ntawm nws qhov kev qhia. Tsis tas li ntawd, qhov nce hauv glucocorticoid secretion tshwm sim los ntawm kev mob tshwm sim tuaj yeem ua rau muaj kev ua haujlwm ntawm lub raum GR hauv cov txiv neej (uas muaj qis dua 11 HSD2 qib) thiab ua rau muaj kev cuam tshuam lwm yam. Zuag qhia tag nrho, cov xwm txheej thaum ntxov perinatal uas yuav tawm tsam lub raum corticosteroid cov kev taw qhia txoj hauv kev tuaj yeem ua rau muaj kev cuam tshuam rau lub sijhawm luv luv thiab mus sij hawm ntev nyob rau hauv ib qho ntawm poj niam txiv neej. Daim duab 3 piav qhia txog lub raum corticosteroid imbalance ntawm kev sib deev lom thiab muaj feem cuam tshuam txog kev loj hlob.

10. Cov lus xaus

Hauv cov ntsiab lus, qhov kev tshuaj xyuas no yog tsom rau kev ua kom pom qhov muaj nyob ntawm lub qhov rais ntawm lub sijhawm thaum lub raum kev loj hlob nrog rau qhov tshwj xeeb thiab lub cev tsis sib xws hauv glucocorticoid thiab mineralocorticoid signaling activation, nrog rau kev sib deev dimorphic kev cai. Qhov kev sib deev sib txawv no thiab kev ua kom lub raum corticosteroid signaling txoj hauv kev hauv cov menyuam hauv plab mammalian thiab neonate, txuag ntawm cov tsiaj, zoo li pom zoo rau mineralocorticoid signaling rau cov poj niam thiab glucocorticoid signaling rau txiv neej. Cov kev sib txawv no tuaj yeem tshwm sim los ntawm kev cuam tshuam ncaj qha lossis tsis ncaj ntawm kev sib deev steroids; Txawm li cas los xij, lwm cov txheej txheem yuav muaj feem cuam tshuam. Kev txiav txim siab txog cov txheej txheem kev tswj hwm no tuaj yeem ua rau pom kev cuam tshuam rau lub sijhawm luv thiab ntev ntawm cov kab mob pathophysiological, ua rau cov txiv neej, thiab pab txhawb kev txhim kho kev tiv thaiv thiab tswj kev sib deev dimorphic kab mob xws li ntshav siab thaum ntxov.

1 Université Paris-Saclay, Inserm, Physiologie thiab Physiopathologie Endocriniennes, CEDEX, 94276 Le Kremlin-Bicêtre, Fabkis; margaux.laulhe@universite-paris-saclay.fr (ML); laurence.dumeige@aphp.fr (LD); thi-an.vu@universite-paris-saclay.fr (TAV); imene.hani@universite-paris-saclay.fr (IH); eric.pussard@aphp.fr (EP);marc.lombes@universite-paris-saclay.fr (ML); say.viengchareun@universite-paris-saclay.fr (SV)

2 Pediatric Endocrinology Department, Hôpital Universitaire Robert Debre, Fabkis & Université de Paris, 75019 Paris, Fabkis

3 Kev Pabcuam ntawm Génétique Moléculaire, Pharmacogénétique thiab Hormonologie, Hôpital de Bicêtre, Kev Pabcuam Publique-Hôpitaux de Paris, 94275 Le Kremlin-Bicêtre, Fabkis

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