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1.
Metabolism ; 160: 155980, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39053691

RESUMO

BACKGROUND: The effect of coronavirus disease 2019 (COVID-19) on adrenal endocrine metabolism in critically ill patients remains unclear. This study aimed to investigate the alterations in adrenal steroidogenic activity, elucidate underlying mechanisms, provide in situ histopathological evidence, and examine the clinical implications. METHODS: The comparative analyses of the adrenal cortices from 24 patients with fatal COVID-19 and 20 matched controls were performed, excluding patients previously treated with glucocorticoids. SARS-CoV-2 and its receptors were identified and pathological alterations were examined. Furthermore, histological examinations, immunohistochemical staining and ultrastructural analyses were performed to assess corticosteroid biosynthesis. The zona glomerulosa (ZG) and zona fasciculata (ZF) were then dissected for proteomic analyses. The biological processes that affected steroidogenesis were analyzed by integrating histological, proteomic, and clinical data. Finally, the immunoreactivity and responsive genes of mineralocorticoid and glucocorticoid receptors in essential tissues were quantitatively measured to evaluate corticosteroid responsiveness. FINDINGS: The demographic characteristics of COVID-19 patients were comparable with those of controls. SARS-CoV-2-like particles were identified in the adrenocortical cells of three patients; however, these particles did not affect cellular morphology or steroid synthesis compared with SARS-CoV-2-negative specimens. Although the adrenals exhibited focal necrosis, vacuolization, microthrombi, and inflammation, widespread degeneration was not evident. Notably, corticosteroid biosynthesis was significantly enhanced in both the ZG and ZF of COVID-19 patients. The increase in the inflammatory response and cellular differentiation in the adrenal cortices of patients with critical COVID-19 was positively correlated with heightened steroidogenic activity. Additionally, the appearance of more dual-ZG/ZF identity cells in COVID-19 adrenals was in accordance with the increased steroidogenic function. However, activated mineralocorticoid and glucocorticoid receptors and their responsive genes in vital tissues were markedly reduced in patients with critical COVID-19. INTERPRETATION: Critical COVID-19 was characterized by potentiated adrenal steroidogenesis, associated with increased inflammation, enhanced differentiation and elevated dual-ZG/ZF identity cells, alongside suppressed corticosteroid responsiveness. These alterations implied the reduced effectiveness of conventional corticosteroid therapy and underscored the need for evaluation of the adrenal axis and corticosteroid sensitivity.


Assuntos
Corticosteroides , COVID-19 , Estado Terminal , Humanos , COVID-19/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Corticosteroides/uso terapêutico , Corticosteroides/biossíntese , Idoso , SARS-CoV-2 , Zona Fasciculada/metabolismo , Zona Fasciculada/efeitos dos fármacos , Receptores de Glucocorticoides/metabolismo , Adulto , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/patologia , Zona Glomerulosa/metabolismo , Zona Glomerulosa/efeitos dos fármacos , Zona Glomerulosa/patologia , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos
2.
J Proteome Res ; 23(8): 3418-3432, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39018382

RESUMO

This study analyzes the extracellular matrix (ECM) signatures of the outer (OF = capsule + subcapsular + zona glomerulosa cells) and inner fractions (IF = zona fasciculata cells) of the rat adrenal cortex, which comprise two distinct microenvironment niches. Proteomic profiles of decellularized OF and IF samples, male and female rats, identified 252 proteins, with 32 classified as ECM-component and ECM-related. Among these, 25 proteins were differentially regulated: 17 more abundant in OF, including Col1a1, Col1a2, Col6a1, Col6a2, Col6a3, Col12a1, Col14a1, Lama5, Lamb2, Lamc1, Eln, Emilin, Fbln5, Fbn1, Fbn2, Nid1, and Ltbp4, and eight more abundant in IF, including Col4a1, Col4a2, Lama2, Lama4, Lamb1, Fn1, Hspg2, and Ecm1. Eln, Tnc, and Nid2 were abundant in the female OF, while Lama2, Lama5, Lamb2, and Lamc1 were more abundant in the male IF. The complex protein signature of the OF suggests areas of tissue stress, stiffness, and regulatory proteins for growth factor signaling. The higher concentrations of Col4a1 and Col4a2 and their role in steroidogenesis should be further investigated in IF. These findings could significantly enhance our understanding of adrenal cortex functionality and its implications for human health and disease. Key findings were validated, and data are available in ProteomeXchange (PXD046828).


Assuntos
Córtex Suprarrenal , Proteínas da Matriz Extracelular , Animais , Feminino , Masculino , Ratos , Proteínas da Matriz Extracelular/metabolismo , Córtex Suprarrenal/metabolismo , Proteômica/métodos , Matriz Extracelular/metabolismo , Zona Glomerulosa/metabolismo , Zona Fasciculada/metabolismo , Proteoma/análise , Proteoma/metabolismo
3.
Mol Cell Endocrinol ; 585: 112176, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38341019

RESUMO

Hyperaldosteronism is often associated with inappropriate aldosterone production and aldosterone synthase (Cyp11b2) expression. Normally, Cyp11b2 expression is limited to the adrenal zona glomerulosa (ZG) and regulated by angiotensin II which signals through Gq protein-coupled receptors. As cells migrate inwards, they differentiate into 11ß-hydroxylase-expressing zona fasciculata (ZF) cells lacking Cyp11b2. The mechanism causing ZG-specific aldosterone biosynthesis is still unclear. We investigated the effect of chronic Gq signaling using transgenic mice with a clozapine N-oxide (CNO)-activated human M3 muscarinic receptor (DREADD) coupled to Gq (hM3Dq) that was expressed throughout the adrenal cortex. CNO raised circulating aldosterone in the presence of a high sodium diet with greater response seen in females compared to males. Immunohistochemistry and transcriptomics indicated disrupted zonal Cyp11b2 expression while Wnt signaling remained unchanged. Chronic Gq-DREADD signaling also induced an intra-adrenal RAAS in CNO-treated mice. Chronic Gq signaling disrupted adrenal cortex zonal aldosterone production associated with ZF expression of Cyp11b2.


Assuntos
Córtex Suprarrenal , Hiperaldosteronismo , Masculino , Feminino , Humanos , Camundongos , Animais , Zona Fasciculada , Aldosterona/metabolismo , Córtex Suprarrenal/metabolismo , Zona Glomerulosa/metabolismo , Citocromo P-450 CYP11B2/genética , Via de Sinalização Wnt , Camundongos Transgênicos
4.
Geroscience ; 46(3): 3405-3417, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38311700

RESUMO

Debate exists on life-course adrenocortical zonal function trajectories. Rapid, phasic blood steroid concentration changes, such as circadian rhythms and acute stress responses, complicate quantification. To avoid pitfalls and account for life-stage changes in adrenocortical activity indices, we quantified zonae fasciculata (ZF) and reticularis (ZR) across the life-course, by immunohistochemistry of key regulatory and functional proteins. In 28 female baboon adrenals (7.5-22.1 years), we quantified 12 key proteins involved in cell metabolism, division, proliferation, steroidogenesis (including steroid acute regulatory protein, StAR), oxidative stress, and glucocorticoid and mitochondrial function. Life-course abundance of ten ZF proteins decreased with age. Cell cycle inhibitor and oxidative stress markers increased. Seven of the 12 proteins changed in the same direction for ZR and ZF. Importantly, ZF StAR decreased, while ZR StAR was unchanged. Findings indicate ZF function decreased, and less markedly ZR function, with age. Causes and aging consequences of these changes remain to be determined.


Assuntos
Zona Fasciculada , Zona Reticular , Feminino , Humanos , Zona Reticular/metabolismo , Zona Fasciculada/metabolismo , Acontecimentos que Mudam a Vida , Esteroides/metabolismo
5.
Endocr J ; 70(12): 1123-1130, 2023 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-37793884

RESUMO

In adrenal fasciculata cells stimulated by ACTH, Ca2+ and cAMP play indispensable roles as second messengers in cortisol production. However, whether their second messengers cooperatively or independently participate in steroid production remains unclear. We focused on the roles of Ca2+ and cAMP in cortisol production in bovine adrenal fasciculata cells stimulated by ACTH for a relatively short period (1 h). Incubation of the cells with 100 pM ACTH in Ca2+-containing (normal) medium for 1 h increased cortisol production without affecting cAMP content. In contrast, treatment of the cells with the peptide at a higher concentration (1 nM) significantly augmented both cortisol production and cAMP content. However, ACTH did not increase either of them in the Ca2+-free medium. ACTH rapidly increased the intracellular free Ca2+ concentration ([Ca2+]i) in the normal medium, but did not influence [Ca2+]i in the Ca2+-free medium, indicating that ACTH caused Ca2+ influx into the cells. ACTH-induced Ca2+ influx and cortisol production were suppressed by a voltage-sensitive L-type Ca2+ channel blocker but not by a T-type, N-type, or P-type Ca2+ channel blocker. In contrast, dibutyryl cAMP, a cell-permeable cAMP analog, greatly enhanced cortisol production in the normal or Ca2+-free medium and slowly caused Ca2+ influx into the cells. These results strongly suggest that Ca2+, as a second messenger, is more critical than cAMP for cortisol production. However, both second messengers jointly participate in the production in adrenal fasciculata cells stimulated by ACTH.


Assuntos
Hidrocortisona , Zona Fasciculada , Animais , Bovinos , Cálcio , Sistemas do Segundo Mensageiro , Hormônio Adrenocorticotrópico/farmacologia , Células Cultivadas
6.
Histochem Cell Biol ; 160(6): 563-576, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37604940

RESUMO

The aim of this study was to reveal the effects of obesity and phytotherapy with 20-hydroxyecdysone (20E) on the nuclei of adrenal zona fasciculata (ZF) in the gerbil Gerbillus tarabuli by analyzing nuclear shape and gray-level co-occurrence matrix (GLCM) texture characteristics and by quantifying heterochromatin. Twelve gerbils were divided into three groups: control (C), HC and HC-20E (animals receiving a high-calorie-diet without or with a supplement of 20E, respectively). The adrenals were removed and fixed for histological and statistical analysis. Principal component analysis showed a positive correlation of area, perimeter and textural correlation in C. Nevertheless, a negative correlation was recorded for contrast and entropy. The obesity caused a disorder in nuclear texture; negative correlation was noted with heterochromatin fraction, which may be related to increased ZF activity. However, administration of 20E seems to improve the nuclear state by preserving circularity, uniformity and homogeneity of nuclei as well as the proportion of heterochromatin, which could be a sign of a downregulation of cell activity.Our results suggest that new techniques of image processing could contribute to the understanding of nuclear changes associated with obesity and its possible therapy in this gerbil model for metabolic syndrome.


Assuntos
Síndrome Metabólica , Zona Fasciculada , Animais , Heterocromatina , Gerbillinae , Ecdisterona , Obesidade
7.
Int J Mol Sci ; 24(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36674444

RESUMO

Steroid hormones are synthesized through enzymatic reactions using cholesterol as the substrate. In steroidogenic cells, the required cholesterol for steroidogenesis can be obtained from blood circulation or synthesized de novo from acetate. One of the key enzymes that control cholesterol synthesis is 24-dehydrocholesterol reductase (encoded by DHCR24). In humans and rats, DHCR24 is highly expressed in the adrenal gland, especially in the zona fasciculata. We recently reported that DHCR24 was expressed in the mouse adrenal gland's inner cortex and also found that thyroid hormone treatment significantly upregulated the expression of Dhcr24 in the mouse adrenal gland. In the present study, we showed the cellular expression of DHCR24 in mouse adrenal glands in early postnatal stages. We found that the expression pattern of DHCR24 was similar to the X-zone marker gene 20αHSD in most developmental stages. This finding indicates that most steroidogenic adrenocortical cells in the mouse adrenal gland do not synthesize cholesterol locally. Unlike the 20αHSD-positive X-zone regresses during pregnancy, some DHCR24-positive cells remain present in parous females. Conditional knockout mice showed that the removal of Dhcr24 in steroidogenic cells did not affect the overall development of the adrenal gland or the secretion of corticosterone under acute stress. Whether DHCR24 plays a role in conditions where a continuous high amount of corticosterone production is needed requires further investigation.


Assuntos
Corticosterona , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Humanos , Camundongos , Feminino , Ratos , Animais , Corticosterona/metabolismo , Glândulas Suprarrenais/metabolismo , Zona Fasciculada/metabolismo , Colesterol/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética
8.
Bull Exp Biol Med ; 173(1): 67-71, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35622248

RESUMO

The article presents the results of histological and bacteriological analysis of the adrenal glands in two models of sepsis caused by intraperitoneal administration of Pseudomonas aeruginosa strains 1623 and 5266 to sexually mature male C57BL/6 mice. In both models, histological changes in the adrenal glands in the dynamics of sepsis consist in cell destruction and decrease in the absolute areas of the zona glomerulosa, columnar part of the zona fasciculata, and medulla, the development of venous congestion in the absence of pronounced signs of leukocytic infiltration. Most adrenocortical cells of the zona glomerulosa and chromaffin cells of the medulla show signs of destruction. The columnar part of the zona fasciculata loses normal architectonics, the cells undergo degeneration and apoptosis, a significant part of cells in the deep layers of the zona fasciculata remain intact, but do not show tinctorial and ultrastructural signs of steroidogenesis. The active growth of P. aeruginosa colonies from adrenal homogenates in both models already in the first hours after infection of animals makes it possible to associate the revealed structural changes in the adrenal glands with the direct negative effect of P. aeruginosa, and high levels of mRNA of proinflammatory cytokines in the adrenal tissues raise the question of the possible synthesis of these modulators of inflammation in the adrenal parenchyma of septic animals.


Assuntos
Córtex Suprarrenal , Sepse , Glândulas Suprarrenais , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Zona Fasciculada , Zona Glomerulosa
9.
Microsc Res Tech ; 85(8): 2813-2825, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35411989

RESUMO

In the present study, we investigated the antioxidant effect of grape seed extract (GSE) against chronic immobilization stress-induced zona fasciculata injury in Wistar male rats. Thirty male rats were divided into three groups: Non-stress group: rats were not subjected to stress protocol and received distilled water orally for 30 days. Stress group: rats received distilled water orally for 15 consecutive days before the induction of chronic immobilization stress experiment (repeated stress for 15 consecutive days), distilled water was continued along with the constant stress experiment. GSE-stress group: rats treated with oral GSE (300 mg/kg), administered orally for 15 consecutive days before the induction of chronic immobilization stress experiment (repeated stress for 15 consecutive days), GSE was continued along with the stress exposure. Chronic stress was induced by placing each animal in a restrainer for 2 h daily for 15 consecutive days in both Stress and GSE-stress groups. The serum corticosterone and adrenal cortex malondialdehyde (MDA) levels were measured as indices of stress. Immunohistochemistry of the inducible nitric oxide synthase (iNOS) as a nitrosative stress marker beside the adrenal cortex's ultrastructure, particularly zona fasciculata, was assessed. Chronic restraint stress significantly elevated the serum corticosterone and adrenal cortex MDA levels, while oral administration of GSE reduced the serum corticosterone level, adrenal cortex MDA levels, and iNOS immunoreactivity in zona fasciculata. Besides, adrenocortical ultrastructure significantly improved. These results suggested that GSE enhanced the antioxidant defense against reactive oxygen species produced under chronic stress conditions, protecting the adrenal cortex. RESEARCH HIGHLIGHTS: This research highlighted the significant protective effects of grape seed extract administration on the histological findings, both in light and electron microscopic studies, as well as the biochemical and functional parameters in cases of stress-induced adrenal cortex injury in rats.


Assuntos
Extrato de Sementes de Uva , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Corticosterona/farmacologia , Elétrons , Extrato de Sementes de Uva/farmacologia , Masculino , Estresse Oxidativo , Ratos , Ratos Wistar , Água , Zona Fasciculada/metabolismo
10.
Tissue Cell ; 75: 101729, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35065350

RESUMO

The adrenals synthesize many hormones involved in the regulation and maintenance of homeostasis. To understand the pathophysiological changes during the development of obesity, a histological study of the adrenal was performed in gerbils receiving a high-fat/high-carbohydrate-diet (HFC) for 8 or 12 weeks. Compared to the controls, the HFC diet increased body weight. Our results reveal significant weight and structural changes in the HFC group's adrenal glands (confirmed by gray level co-occurrence matrix texture and fractal analysis), disorganization of zona fasciculata (8 weeks) and hyperplasia and peri-capillary fibrosis (12 weeks). In conclusion, these results show that an HFC induces time-dependent structural lesions of the adrenals in gerbils, which could be a sign of chronic adaptation of these glands.


Assuntos
Glândulas Suprarrenais , Zona Fasciculada , Animais , Carboidratos , Dieta Hiperlipídica/efeitos adversos , Gerbillinae , Zona Fasciculada/patologia
11.
Microsc Res Tech ; 85(2): 738-747, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34553804

RESUMO

This research was aimed to present the histological and ultrastructure properties of the adrenal gland in the Persian squirrel. Two male and female animals were included in the study. The adrenal gland was bean-shaped and located on the cranial pole of kidney. The enveloping capsule was dense connective tissue that reacted positively with Periodic-Acid Schiff (PAS) and Masson trichrome stainings. The parenchyma of the gland consisted of two-part, namely cortex and medulla; the cortex had three layers: zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR). The cells of the ZG were mainly spherical and ovoid with circular arrangement and few lipid droplets in TEM micrographs. The cells of the ZF were columnar and spherical that were arranged in cord-like rows. Transmission electron microscopy (TEM) indicated conspicuous lipid droplets and mitochondria in this zone. The cells of the ZR were arranged in a tangled networks and were almost similar to those in the ZF. TEM images showed fewer lipid vesicles in the ZR compared to the ZF and ZG. Chromaffin cells were located in the medulla of the adrenal gland in two layers. TEM images showed that some of them were smaller and contained fewer secretory granules; other cells were larger and contained more electron-dense secretory granules. Immunofluorescence staining showed that steroidogenic factor 1 (SF1) expressed from cortex to the corticomedullary junction (CMJ) and tyrosine hydroxylase (TH) expressed in the medulla. In conclusion, the results indicated both similarities and differences between the adrenal gland of the Persian squirrel and other animals such as mammals and rodents.


Assuntos
Elétrons , Sciuridae , Glândulas Suprarrenais , Animais , Feminino , Masculino , Microscopia Eletrônica de Transmissão , Zona Fasciculada
12.
Int J Mol Sci ; 22(24)2021 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-34948031

RESUMO

BACKGROUND: Rats exposed to chronic predator scent stress mimic the phenotype of complex post-traumatic stress disorder (PTSD) in humans, including altered adrenal morphology and function. High- and low-anxiety phenotypes have been described in rats exposed to predator scent stress (PSS). This study aimed to determine whether these high- and low-anxiety phenotypes correlate with changes in adrenal histomorphology and corticosteroid production. METHODS: Rats were exposed to PSS for ten days. Thirty days later, the rats' anxiety index (AI) was assessed with an elevated plus-maze test. Based on differences in AI, the rats were segregated into low- (AI ≤ 0.8, n = 9) and high- (AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone (CORT) concentrations were measured by ELISA. Adrenal CORT, desoxyCORT, and 11-dehydroCORT were measured by high-performance liquid chromatography. After staining with hematoxylin and eosin, adrenal histomorphometric changes were evaluated by measuring the thickness of the functional zones of the adrenal cortex. RESULTS: Decreased plasma CORT concentrations, as well as decreased adrenal CORT, desoxyCORT and 11-dehydroCORT concentrations, were observed in high- but not in low-anxiety phenotypes. These decreases were associated with increases in AI. PSS led to a significant decrease in the thickness of the zona fasciculata and an increase in the thickness of the zona intermedia. The increase in the thickness of the zona intermedia was more pronounced in low-anxiety than in high-anxiety rats. A decrease in the adrenal capsule thickness was observed only in low-anxiety rats. The nucleus diameter of cells in the zona fasciculata of high-anxiety rats was significantly smaller than that of control or low-anxiety rats. CONCLUSION: Phenotype-associated changes in adrenal function and histomorphology were observed in a rat model of complex post-traumatic stress disorder.


Assuntos
Glândulas Suprarrenais/fisiopatologia , Corticosterona/metabolismo , Transtornos de Estresse Pós-Traumáticos/patologia , Estresse Psicológico/complicações , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/patologia , Animais , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Corticosterona/análogos & derivados , Corticosterona/sangue , Desoxicorticosterona/sangue , Desoxicorticosterona/metabolismo , Modelos Animais de Doenças , Fenótipo , Ratos , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/metabolismo , Zona Fasciculada/metabolismo , Zona Fasciculada/patologia , Zona Fasciculada/fisiopatologia
13.
J Clin Endocrinol Metab ; 106(5): 1389-1397, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33524149

RESUMO

BACKGROUND: While previous studies indicate that the zonae reticularis (ZR) and glomerulosa (ZG) diminish with aging, little is known about age-related transformations of the zona fasciculata (ZF). OBJECTIVES: To investigate the morphological and functional changes of the adrenal cortex across adulthood, with emphasis on (i) the understudied ZF and (ii) sexual dimorphisms. METHODS: We used immunohistochemistry to evaluate the expression of aldosterone synthase (CYP11B2), visinin-like protein 1 (VSNL1), 3ß-hydroxysteroid dehydrogenase type II (HSD3B2), 11ß-hydroxylase (CYP11B1), and cytochrome b5 type A (CYB5A) in adrenal glands from 60 adults (30 men), aged 18 to 86. Additionally, we employed mass spectrometry to quantify the morning serum concentrations of cortisol, 11-deoxycortisol (11dF), 17α-hydroxyprogesterone, 11-deoxycorticosterone, corticosterone, and androstenedione in 149 pairs of age- and body mass index-matched men and women, age 21 to 95 years. RESULTS: The total cortical area was positively correlated with age (r = 0.34, P = 0.008). Both the total (VSNL1-positive) and functional ZG (CYP11B2-positive) areas declined with aging in men (r = -0.57 and -0.67, P < 0.01), but not in women. The CYB5A-positive area declined with age in both sexes (r = -0.76, P < 0.0001). In contrast, the estimated ZF area correlated positively with age in men (r = 0.59, P = 0.0006) and women (r = 0.49, P = 0.007), while CYP11B1-positive area remained unchanged across ages. Serum cortisol, corticosterone, and 11-deoxycorticosterone levels were stable across ages, while 11dF levels increased slightly with age (r = 0.16, P = 0.007). CONCLUSION: Unlike the ZG and ZR, the ZF and the total adrenal cortex areas enlarge with aging. An abrupt decline of the ZG occurs with age in men only, possibly contributing to sexual dimorphism in cardiovascular risk.


Assuntos
Córtex Suprarrenal/patologia , Córtex Suprarrenal/fisiologia , Envelhecimento/fisiologia , Adolescente , Córtex Suprarrenal/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Estudos de Casos e Controles , Citocromo P-450 CYP11B2/metabolismo , Citocromos b5/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Progesterona Redutase/metabolismo , Esteroide 11-beta-Hidroxilase/metabolismo , Esteroide 17-alfa-Hidroxilase/metabolismo , Adulto Jovem , Zona Fasciculada/metabolismo , Zona Fasciculada/patologia , Zona Glomerulosa/metabolismo , Zona Glomerulosa/patologia , Zona Reticular/metabolismo , Zona Reticular/patologia
14.
Mol Cell Endocrinol ; 526: 111195, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33571577

RESUMO

The hypothalamic-pituitary-adrenal axis is the primary neuroendocrine system activated to re-establish homeostasis during periods of stress, including critical illness and major surgery. During critical illness, evidence suggests that locally induced inflammation of the adrenal gland could facilitate immune-adrenal cross-talk and, in turn, modulate cortisol secretion. It has been hypothesized that immune cells are necessary to mediate the effect of inflammatory stimuli on the steroidogenic pathway that has been observed in vivo. To test this hypothesis, we developed and characterized a trans-well co-culture model of THP1 (human monocytic cell)-derived macrophages and ATC7 murine zona fasciculata adrenocortical cells. We found that co-culture of ATC7 and THP1 cells results in a significant increase in the basal levels of IL-6 mRNA in ATC7 cells, and this effect was potentiated by treatment with LPS. Addition of LPS to co-cultures of ATC7 and THP1 significantly decreased the expression of key adrenal steroidogenic enzymes (including StAR and DAX-1), and this was also found in ATC7 cells treated with pro-inflammatory cytokines. Moreover, 24-h treatment with the synthetic glucocorticoid dexamethasone prevented the effects of LPS stimulation on IL-6, StAR and DAX-1 mRNA in ATC7 cells co-cultured with THP1 cells. Our data suggest that the expression of IL-6 and steroidogenic genes in response to LPS depends on the activation of intra-adrenal immune cells. Moreover, we also show that the effects of LPS can be modulated by glucocorticoids in a time- and dose-dependent manner with potential implications for clinical practice.


Assuntos
Sistema Imunitário/metabolismo , Modelos Biológicos , Monócitos/citologia , Zona Fasciculada/citologia , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Dexametasona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Monócitos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esteroides/metabolismo , Células THP-1 , Fatores de Tempo
15.
Thyroid ; 31(6): 861-869, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33126831

RESUMO

Background: The fetal hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the control of parturition and maturation of organ systems in preparation for birth. In hypothyroid fetuses, gestational length may be prolonged and maturational processes delayed. The extent to which the effects of thyroid hormone deficiency in utero on the timing of fetal maturation and parturition are mediated by changes to the structure and function of the fetal HPA axis is unknown. Methods: In twin sheep pregnancies where one fetus was thyroidectomized and the other sham-operated, this study investigated the effect of hypothyroidism on circulating concentrations of adrenocorticotrophic hormone (ACTH) and cortisol, and the structure and secretory capacity of the anterior pituitary and adrenal glands. The relative population of pituitary corticotrophs and the masses of the adrenal zones were assessed by immunohistochemical and stereological techniques. Adrenal mRNA abundances of key steroidogenic enzymes and growth factors were examined by quantitative polymerase chain reaction. Results: Hypothyroidism in utero reduced plasma concentrations of ACTH and cortisol. In thyroid-deficient fetuses, the mass of corticotrophs in the anterior pituitary gland was unexpectedly increased, while the mass of the zona fasciculata and its proportion of the adrenal gland were decreased. These structural changes were associated with lower adrenocortical mRNA abundances of insulin-like growth factor (IGF)-I and its receptor, and key steroidogenic enzymes responsible for glucocorticoid synthesis. The relative mass of the adrenal medulla and its proportion of the adrenal gland were increased by thyroid hormone deficiency in utero, without any change in expression of phenylethanolamine N-methyltransferase or the IGF system. Conclusions: Thyroid hormones are important regulators of the structure and secretory capacity of the pituitary-adrenal axis before birth. In hypothyroid fetuses, low plasma cortisol may be due to impaired adrenocortical growth and steroidogenic enzyme expression, secondary to low circulating ACTH concentration. Greater corticotroph population in the anterior pituitary gland of the hypothyroid fetus indicates compensatory cell proliferation and that there may be abnormal corticotroph capacity for ACTH synthesis and/or impaired hypothalamic input. Suppression of the development of the fetal HPA axis by thyroid hormone deficiency may contribute to the delay in fetal maturation and delivery observed in hypothyroid offspring.


Assuntos
Corticosteroides/metabolismo , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Hipotireoidismo Congênito/metabolismo , Corticotrofos/metabolismo , Desenvolvimento Fetal/fisiologia , Doenças Fetais/metabolismo , Tireoidectomia , Glândulas Suprarrenais/patologia , Medula Suprarrenal/metabolismo , Medula Suprarrenal/patologia , Animais , Contagem de Células , Proliferação de Células , Hipotireoidismo Congênito/patologia , Corticotrofos/patologia , Doenças Fetais/patologia , Maturidade dos Órgãos Fetais , Hidrocortisona/sangue , Sistema Hipotálamo-Hipofisário/metabolismo , Fator de Crescimento Insulin-Like I/genética , Sistema Hipófise-Suprarrenal/metabolismo , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/genética , Ovinos , Tiroxina/deficiência , Tiroxina/metabolismo , Tri-Iodotironina/deficiência , Tri-Iodotironina/metabolismo , Zona Fasciculada/metabolismo , Zona Fasciculada/patologia
16.
Hypertension ; 76(6): 1769-1777, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33070662

RESUMO

Primary aldosteronism is a frequent form of endocrine hypertension caused by aldosterone overproduction from the adrenal cortex. Regulation of aldosterone biosynthesis has been studied in rodents despite differences in adrenal physiology with humans. We, therefore, investigated pig adrenal steroidogenesis, morphology, and transcriptome profiles of the zona glomerulosa (zG) and zona fasciculata in response to activation of the renin-angiotensin-aldosterone system by dietary sodium restriction. Six-week-old pigs were fed a low- or high-sodium diet for 14 days (3 pigs per group, 0.4 g sodium/kg feed versus 6.8 g sodium/kg). Plasma aldosterone concentrations displayed a 43-fold increase (P=0.011) after 14 days of sodium restriction (day 14 versus day 0). Low dietary sodium caused a 2-fold increase in thickness of the zG (P<0.001) and an almost 3-fold upregulation of CYP11B (P<0.05) compared with high dietary sodium. Strong immunostaining of the KCNJ5 (G protein-activated inward rectifier potassium channel 4), which is frequently mutated in primary aldosteronism, was demonstrated in the zG. mRNA sequencing transcriptome analysis identified significantly altered expression of genes modulated by the renin-angiotensin-aldosterone system in the zG (n=1172) and zona fasciculata (n=280). These genes included many with a known role in the regulation of aldosterone synthesis and adrenal function. The most highly enriched biological pathways in the zG were related to cholesterol biosynthesis, steroid metabolism, cell cycle, and potassium channels. This study provides mechanistic insights into the physiology and pathophysiology of aldosterone production in a species closely related to humans and shows the suitability of pigs as a translational animal model for human adrenal steroidogenesis.


Assuntos
Córtex Suprarrenal/efeitos dos fármacos , Dieta Hipossódica/métodos , Sódio na Dieta/farmacologia , Esteroides/metabolismo , Transcriptoma/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Aldosterona/metabolismo , Animais , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Masculino , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/genética , Sódio na Dieta/administração & dosagem , Sódio na Dieta/metabolismo , Suínos , Transcriptoma/genética , Zona Fasciculada/efeitos dos fármacos , Zona Fasciculada/metabolismo , Zona Glomerulosa/efeitos dos fármacos , Zona Glomerulosa/metabolismo
17.
Endocrinology ; 161(9)2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32697836

RESUMO

The sex-specific prevalence of adrenal diseases has been known for a long time. However, the reason for the high prevalence of these diseases in females is not completely understood. Mouse studies have shown that the adult adrenal gland is sexually dimorphic at different levels such as transcriptome, histology, and cell renewal. Here we used RNA-seq to show that in prepubertal mice, male and female adrenal glands were not only sexually dimorphic but also responded differently to the same external stimulus. We previously reported that thyroid hormone receptor ß1 (TRß1) in the adrenal gland is mainly expressed in the inner cortex and the fate of this TRß1-expressing cell population can be changed by thyroid hormone (triiodothyronine; T3) treatment. In the present study, we found that adrenal glands in prepubertal mice were sexually dimorphic at the level of the transcriptome. Under T3 treatment, prepubertal females had 1162 genes differentially expressed between the saline and T3 groups, whereas in males of the same age, only 512 genes were T3-responsive. Immunostaining demonstrated that several top sexually dimorphic T3-responsive genes, including Cyp2f2 and Dhcr24, were specifically expressed in the adrenal inner cortex, precisely in an area partially overlapping with the X-zone. Under T3 treatment, a unique cortical layer that surrounds the adrenal X-zone expanded significantly, forming a distinct layer peculiar to females. Our findings identified novel marker genes for the inner adrenal cortex, indicating there are different sub-zones in the zona fasciculata. The results also highlight the sex-specific response to thyroid hormone in the mouse adrenal gland.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Hormônios Tireóideos/farmacologia , Zona Fasciculada/efeitos dos fármacos , Zona Fasciculada/metabolismo , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Animais , Feminino , Perfilação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA-Seq , Caracteres Sexuais , Distribuição Tecidual/efeitos dos fármacos
18.
Sheng Li Xue Bao ; 72(2): 148-156, 2020 Apr 25.
Artigo em Chinês | MEDLINE | ID: mdl-32328608

RESUMO

The adrenal gland is an important endocrine organ of human body. CYP11B1 gene was specifically expressed in the zona fasciculata in adrenal cortex. In order to better study the function of genes specifically expressed in the zona fasciculata in adrenal cortex, the mice with Cre recombinase specifically expressed in the zona fasciculata in adrenal cortex were constructed. It was then confirmed that CYP11B1 was specifically expressed in adrenal glands. Then, using CRISPR/Cas9 technique, CYP11B1-2A-GfpCre recombinant vector was constructed and subsequently injected into the fertilized eggs of mice. It was confirmed that the Cre gene was mainly expressed in the zona fasciculata in adrenal cortex of CYP11B1Cre mice by using mTmG and LacZ staining. The CYP11B1Cre mice were then mated with cystathionine γ-lyase (CTH)f/f mice, thereby generating CTHf/f/CYP11B1Cre mice. It was also confirmed that CTH gene in the zona fasciculata in adrenal cortex was specifically knocked out in these mice. These results suggest that transgenic mice with specific Cre recombinase expression in the zona fasciculata in adrenal cortex were constructed successfully. This animal model can be a powerful tool for the study of the function of genes expressed in the zona fasciculata in adrenal cortex.


Assuntos
Córtex Suprarrenal/enzimologia , Integrases/metabolismo , Camundongos Transgênicos , Zona Fasciculada/enzimologia , Animais , Sistemas CRISPR-Cas , Cistationina gama-Liase/genética , Integrases/genética , Camundongos
19.
Bull Exp Biol Med ; 168(6): 797-801, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32328948

RESUMO

We studied the expression of transcriptional factors regulating postnatal morphogenesis of the adrenal zona fasciculata in rats after developmental exposure to endocrine disruptor DDT. It was found that tissue reparation after trophic disorders and cell death triggered by prenatal and postnatal exposure to DDT was accompanied by an increase in the number of Oct4- and Shh-expressing cells forming a pool located outside the regeneration zones and involved in the maintenance of tissue homeostasis in the zona fasciculata. DDT exposure also disrupted the expression of antiproliferative factor Hhex. The data showed that proliferation of fasciculata cells after termination of adrenal cortex growth was downregulated by inhibition of the expression of Oct4 and Shh and suppression of canonical Wnt signaling, i.e. due to a decrease in the reserve cell pool essential for physiological regeneration, which can reduce the reactive potential of the zona fasciculata.


Assuntos
DDT/farmacologia , Células Endócrinas/efeitos dos fármacos , Disruptores Endócrinos/farmacologia , Efeitos Tardios da Exposição Pré-Natal/genética , Transcrição Gênica/efeitos dos fármacos , Zona Fasciculada/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Células Endócrinas/citologia , Células Endócrinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Masculino , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Ratos , Ratos Wistar , Via de Sinalização Wnt , Zona Fasciculada/citologia , Zona Fasciculada/crescimento & desenvolvimento , Zona Fasciculada/metabolismo
20.
Eur J Pharmacol ; 872: 172978, 2020 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-32014487

RESUMO

Evidences from human and animal studies indicate that exposure to infection during early life act as a stressor to impair the hypothalamic-pituitary-adrenal (HPA) axis and may be one of the contributing factors of mental illness of later life. Several atypical antipsychotic drugs (AAPDs) proved to be effective in alleviating psychiatric illness through normalization of HPA axis. However, AAPD are least tried to evaluate their efficacy in modulation of HPA axis impaired under infection. The present study elucidated that the treatment with AAPD paliperidone (PAL: 0.025 mg/kg/bw and 0.05 mg/kg/bw) during periadolescence period (postnatal day 35- postnatal day 56) dose-dependently normalized the HPA axis of the female mice who were gestationally (gestational day 15 and 17) exposed to bacterial endotoxin lipopolysaccharide (LPS: 800 µg/kg/bw; intraperitoneally). The effectiveness of PAL treatment in counteracting the LPS induced hyperactivity of HPA axis was age-related, better observed at postnatal day 120 than at postnatal day 200. The PAL modulation of HPA axis reflected at different levels: inhibition of hypothalamic CRF expression and reduction in plasma levels of adrenocorticotropin and corticosterone. Histopathological alterations such as hypertrophy and/or hyperplasia in cortical zona fasciculata as well as medullary chromaffin cells of adrenal also normalized on PAL treatment. The comparatively long wash out period after drug treatment (postnatal day 57- postnatal day 200) along with age related hormonal imbalance could be correlated to less effectiveness of PAL on HPA axis at postnatal day 200. PAL modulation of HPA axis might be through maintenance of cytokines and reproductive axis homeostasis.


Assuntos
Antipsicóticos/administração & dosagem , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Transtornos Mentais/tratamento farmacológico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Complicações Infecciosas na Gravidez/imunologia , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Adolescente , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Fatores Etários , Animais , Células Cromafins/efeitos dos fármacos , Células Cromafins/metabolismo , Corticosterona/sangue , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Lipopolissacarídeos/imunologia , Masculino , Transtornos Mentais/sangue , Transtornos Mentais/imunologia , Transtornos Mentais/fisiopatologia , Camundongos , Palmitato de Paliperidona/administração & dosagem , Sistema Hipófise-Suprarrenal/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Adulto Jovem , Zona Fasciculada/efeitos dos fármacos , Zona Fasciculada/metabolismo , Zona Fasciculada/patologia
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