Adrenal Stress Response Research Articles

Embryo number and periconceptional undernutrition in the sheep have differential effects on adrenal epigenotype, growth, and development.

Exposure to poor maternal nutrition around the time of conception results in an early prepartum activation of the fetal pituitary-adrenal axis and in increased adrenal growth and stress response after birth associated with epigenetic changes in a differentially methylated region (DMR) of adrenal IGF2/H19. We have determined the effects of maternal undernutrition during the periconceptional period (PCUN: 70% of control intake from 60 days before until 6 days after conception) and early preimplantation period (PIUN: 70% of control intake for 6 days after conception) on fetal plasma ACTH and cortisol concentrations and fetal adrenal ACTHR, StAR, 3βHSD, CYP11B, CYP17, TGFβ1, IGF1, IGF1R, IGF2, and IGF2R mRNA expression and the methylation level of sites within the DMRs of IGF2/H19 and IGF2R in the adrenal of twin and singleton fetuses at 136-138 days gestation. Being a twin resulted in a delayed prepartum increase in fetal ACTH and in a lower cortisol response to CRH in the control but not PCUN and PIUN groups. PCUN, but not PIUN, resulted in an increase in adrenal weight and CYP17 expression in singletons, a decrease in adrenal IGF2 expression in singletons, and an increase in adrenal IGF2R expression in both twins and singletons. IGF2/H19 and IGF2R DMR methylation levels and ACTHR expression were lower in the twin adrenal. Thus, exposure of the oocyte and embryo to maternal undernutrition or to the environment of a twin pregnancy have differential effects on epigenetic and other factors that regulate fetal adrenal growth and IGF2 and IGF2R expression.

Long-acting neuroleptic use for reproductive management of non-domestic ungulates using the domestic goat (Capra hircus) as a model

Fluphenazine decanoate is a long-acting phenothiazine neuroleptic that attenuates the stress response and may be useful during intensive handling for reproductive procedures in non-domestic ungulates. However, phenothiazines are also associated with elevated serum prolactin, which can suppress fertility in some species. For this study, 10 female domestic goats were used as a model for non-domestic caprids to test effects of fluphenazine decanoate on serum cortisol and reproductive cyclicity following estrus synchronization. Two identical trials were conducted during the breeding season, employing a random crossover design. First, females underwent estrus synchronization using a 14-day treatment with progesterone (330 mg; CIDR). After 7 days of CIDR exposure, the treatment group (n = 5) received fluphenazine decanoate (1.0 mg/kg IM) and controls (n = 5) received an equivalent volume of 0.9% saline IM. At CIDR withdrawal (Day 14), animals received 125 mg cloprostenol sodium to lyse any luteal tissue and synchronize estrus. Blood was collected every 2 hr from 36 hr after CIDR withdrawal until 24 hr after standing estrus, or up to 5 days to monitor stress and reproductive hormones. Serum cortisol, prolactin, luteinizing hormone (LH) and progesterone concentrations were determined by enzyme immunoassay. While treatment with fluphenazine was associated with lower cortisol concentrations compared to controls (P = 0.001), 4 of the 10 treated animals experienced elevated serum prolactin, suppression of the LH surge and inhibition of ovulation. These findings suggest that long-acting neuroleptic drugs reduce the adrenal stress response, but may interfere with reproductive responses and negatively influence breeding success.

Hydrocortisone Reduces the Beneficial Effects of Toll-Like Receptor 2 Deficiency on Survival in a Mouse Model of Polymicrobial Sepsis

Toll-like receptors (TLRs) play a crucial role in early host defense against microorganisms. Toll-like receptor 2 (TLR2) polymorphisms have a prevalence of 10%; functional defects of TLR2 are associated with higher susceptibility toward gram-positive bacteria, and TLR2 deficiency has been associated with an impaired adrenal stress response. In the present study, we compared endogenous corticosterone production of wild-type (WT) and TLR2-deficient (TLR2) mice and analyzed survival after hydrocortisone therapy during sepsis induced by cecal ligation and puncture (CLP). Male C57BL/6J (WT); and B6.129-Tlr2tm1Kir/J (TLR2) mice were subjected to CLP or sham operation and randomly assigned to postoperative treatment with either hydrocortisone (5 mg/kg) or vehicle (n = 10 mice/group). Survival was documented for an observation period of 48 h. Endogenous corticosterone production following hydrocortisone treatment and lipoteichoic acid (LTA) exposure, interleukin 6 (IL-6) and IL-1β plasma levels, and blood counts were determined following sham operation or CLP using another n = 5 mice/group. Statistical analysis was performed using analysis of variance/Bonferroni. TLR2 mice exhibited a lack of suppression and an attenuated increase in endogenous corticosterone production following hydrocortisone or LTA treatment, respectively. After CLP, TLR2 mice exhibited an uncompromised adrenal stress response, higher IL-6 levels, and increased survival compared with WT controls (75 vs. 35%; P < 0.05). Hydrocortisone therapy of TLR2 mice completely abolished this advantage (decrease in survival to 45%, P < 0.05 vs. vehicle-treated TLR2 mice) and was associated with decreased IL-1β plasma concentrations. Toll-like receptor 2 deficiency is associated with an uncompromised adrenal stress response and increased survival rates during polymicrobial sepsis. Hydrocortisone treatment increases mortality of septic TLR2 mice, suggesting that hydrocortisone therapy might be harmful for individuals with functional TLR2 polymorphisms.

Dietary restriction in the periconceptional period in normal-weight or obese ewes results in increased abundance of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor (AT1R) in the absence of changes in ACE or AT1R methylation in the adrenal of the offspring

Exposure to dietary restriction during the periconceptional period in either normal or obese ewes results in increased adrenal growth and a greater cortisol response to stress in the offspring, but the mechanisms that programme these changes are not fully understood. Activation of the angiotensin type 1 receptor (AT1R) has been demonstrated to stimulate adrenal growth and steroidogenesis. We have used an embryo transfer model in the sheep to investigate the effects of exposure to dietary restriction in normal or obese mothers from before and 1 week after conception on the methylation status, expression, abundance and localisation of key components of the renin-angiotensin system (RAS) in the adrenal of post-natal lambs. Maternal dietary restriction in normal or obese ewes during the periconceptional period resulted in an increase in angiotensin-converting enzyme (ACE) and AT1R abundance in the absence of changes in the methylation status or mRNA expression of ACE and AT1R in the adrenal of the offspring. Exposure to maternal obesity alone also resulted in an increase in adrenal AT1R abundance. There was no effect of maternal dietary restriction or obesity on ACE2 and AT2R or on ERK, calcium/calmodulin-dependent kinase II abundance, and their phosphorylated forms in the lamb adrenal. Thus, weight loss around the time of conception, in both normal-weight and obese ewes, results in changes within the intra-adrenal RAS consistent with increased AT1R activation. These changes within the intra-adrenal RAS system may contribute to the greater adrenal stress response following exposure to signals of adversity in the periconceptional period.

152. Cortisol reacitivity and body mass index in pre-adolescent children

Background Considerable research has focused on alterations in the hypothalamic–pituitary–adrenal (HPA) stress response and obesity in adults, with most studies reporting an association of increased body mass index (BMI) with increased HPA activity. Early detection of HPA alterations in younger children with increased BMI is critical for targeted intervention and prevention of later adverse health outcomes. This study examines the association of body mass index (BMI) with HPA reactivity to an acute stressor in pre-adolescent children, and further, whether the relationship is influenced by the presence of anxiety or depression. METHODS: A social evaluative Cold Pressor Task was used to elicit an acute stress response among children aged 8–12 years ( n = 43). Repeated saliva samples were assayed for cortisol to determine area under the curve with respect to increase (AUCi) and ground (AUCg). Anxiety and depressive symptoms were assessed with standardized measures. Bivariate correlational analyses examined relationships of BMI with AUCi/AUCg; linear regression assessed a combined model of BMI and anxiety/depressive symptoms predicting AUCi/AUCg. RESULTS: BMI was inversely associated with AUCg ( r = −.47, p = .002) but not with AUCi ( r = −.04, p = .79); this relationship remained significant in the multiple regression model. Conclusions : The relationship between BMI and HPA reactivity may differ in children vs. adults. Results additionally underscore the need to assess both cortisol output (AUCg) and HPA reactivity (AUCi) in these investigations.

Maturation-dependent behavioral deficits and cell injury in developing animals during the subacute postictal period

Prolonged early-life seizures are associated with disruptions of affective and cognitive function. Postictal disturbances, temporary functional deficits that persist for hours to days after seizures, have not yet been thoroughly characterized. Here, we used kainic acid (KA) to induce status epilepticus (SE) in immature rats at three developmental stages (postnatal day (P) 15, 21, or 30) and subsequently assessed spatial learning and memory in a Barnes maze, exploratory behavior in an open field, and the spatiotemporal distribution of cell injury during the first 7–10days of the postictal period. At 1day post-SE, P15-SE rats showed no deficit in the Barnes maze but were hyperexploratory in an open field compared with their littermate controls. In contrast, P21- and P30-SE rats exhibited markedly impaired performance in the Barnes maze and exhibited significantly reduced open field exploration suggestive of anxiety-like behavior. These behavioral changes were transient in P15 rats but more persistent in P21 and enduring in P30 rats after KA-SE. The time course of behavioral deficits in P21 and P30 rats was temporally correlated with the presence of neuronal injury in the lateral septal nuclei, amygdala, and ventral subiculum/CA1, regions involved in modulation of the hypothalamic–pituitary–adrenal stress response.

Effects of chronic swim stress on endocrine and cardiac function in angiotensin AT1a receptor knockout mice

Stress increases circulating angiotensin II (AngII) which contributes to stimulation of adrenal Ang type 1 receptors (AT1R), mediating stress‐induced hormone release. The goal was to assess the influence of chronic swim stress on adrenal and cardiac function in AT1aR knockout mice. Adult male AT1R knockout (KO) and wild type (WT) mice (n=6) were used; groups were exercise (KO and WT) and sedentary (KO and WT). Exercise paradigm was swimming, 1 hour 3d/wk for 7 weeks. Urine and plasma corticosterone (CORT) were measured by RIA. Cardiac function was assessed by echocardiography (Echo). Results showed that plasma CORT was lower in chronic exercise as compared to sedentary groups (3 fold decrease). Urinary CORT was used to show the dynamic response to exercise stress. The stimulatory change was 10 fold higher in WTEX as compared to 5 fold in KOEX. Echo showed a higher ejection fraction (EF%) in KOEX (75%) vs. WTEX (55%). Assessment of mitral valve function showed a higher A‐wave velocity in KOEX as compared to WTEX. Ang AT1aR deficient mice showed improved cardiac response and reduced adrenal stress response to chronic exercise.

Postmenopausal sex hormones: comparing apples and pears

Postmenopausal sex hormones: comparing apples and pears

157. Anticipatory stress appraisal is differentially associated with HPA and immune acute stress responses in children with anxiety disorders

Background: Increasing research has focused on the association of alterations in hypothalamic–pituitary–adrenal (HPA) and immune stress response systems with anxiety. This study examines the influence of state cognitive stress appraisal on these relationships. Methods: A social evaluative Cold Pressor Task (CPT) was used to elicit stress among children aged 8–12 years with an anxiety disorder (“Cases” n = 21) and healthy controls (“Controls” n = 22). Repeated saliva samples were assayed for cortisol and S-IgA to determine area under the curve (AUC) and Peak Response. Measures of anticipatory anxiety to the CPT included (1) Brief Fear of Negative Evaluation Scale (BFNE-II) and (2) Primary Appraisal Secondary Appraisal Scale (PASA). Groups were compared on biological and cognitive variables via t -tests; Pearson correlations examined relationships among cognitive variables, cortisol, and IgA within groups. Results: There were no group differences in cortisol or IgA (AUC; Peak Response), BFNE-II, or PASA. Within Cases, S-IgA AUC and Peak Response had significant negative associations with BFNE ( r = −.73, p r = −.52; p = .018, respectively) and PASA-Threat ( r = −.58, p = .006; r = −.61; p = .003, respectively), whereas only cortisol Peak Response had a significant positive association with PASA-Threat ( r = .48, p = .032); associations were not significant in Controls. Conclusions: Children with anxiety disorders who appraise acute situations as more threatening and negatively evaluative may be at increased risk for aberrant HPA and immune stress responses to acute stress.

Assessment of central adrenal insufficiency in children and adolescents with Prader–Willi syndrome

A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader-Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low-Dose Tetracosactrin Stimulation Test (LDTST), 1 μg] or standard-dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS. Cross-sectional evaluation of adrenal stress response to LDTST in a PWS cohort of a tertiary care referral centre. Eighty-four children with PWS. Assessment of adrenal response by morning cortisol and ACTH dosage, and 1-μg tetracosactrin test. Response was considered appropriate when cortisol reached 500 nm; below this threshold, patients were submitted to a second test. Responses were correlated with the patients' clinical and molecular characteristics to assess genotype-phenotype correlation. Pathological cortisol peak responses to the LDTST were registered in 12 patients (14.3%) who had reduced basal (169.4 ± 83.3 nm) and stimulated (428.1 ± 69.6 nm) cortisol levels compared to patients with normal responses (367.1 ± 170.6 and 775.9 ± 191.3 nm, P < 0.001). Body mass index standard deviation score was negatively correlated with basal and peak cortisol levels (both P < 0.001), and the patients' ages (P < 0.001). In patients with deletion on chromosome 15, the cortisol peak was significantly lower than that in uniparental disomy (UPD) cases (P = 0.030). At multiple regression analysis, the predictors of peak response were basal cortisol, age, and UPD subclass (r(2) = 0.353, P < 0.001). Standard-dose (250 μg) tetracosactrin test confirmed CAI in 4/12 patients (4.8% of the cohort). Our results support the hypothesis that, albeit rare, CAI may be part of the PWS in childhood.

Urocortin-dependent effects on adrenal morphology, growth, and expression of steroidogenic enzymes in vivo

Urocortin (UCN) 1, 2, and 3 are members of the corticotropin-releasing factor (CRF) family that display varying affinities to the CRF receptor 1 (CRFR1 (CRHR1)) and 2 (CRFR2 (CRHR2)). UCNs represent important modulators of stress responses and are involved in the control of anxiety and related disorders. In addition to the CNS, UCNs and CRFRs are highly expressed in several tissues including the adrenal gland, indicating the presence of UCN-dependent regulatory mechanisms in these peripheral organ systems. Using knockout (KO) mouse models lacking single or multiple Ucn genes, we examined the potential role of the three different Ucns on morphology and function of the adrenal gland. Adrenal morphology was investigated, organ size, cell size, and number were quantified, and growth kinetics were studied by proliferative cell nuclear antigen staining and Ccnd1 expression analysis. Furthermore, mRNA expression of enzymes involved in steroidogenesis and catecholamine synthesis was quantified by real-time PCR. Following this approach, Ucn2, Ucn1/Ucn2 dKO and Ucn1/Ucn2/Ucn3 tKO animals showed a significant cellular hypotrophy of the adrenal cortex and an increase in Ccnd1 expression, whereas in all other genotypes, no changes were observable in comparison to age-matched controls. For steroidogenesis, Ucn2/Ucn3 dKO animals displayed the most pronounced changes, with significant increases in all investigated enzymes, providing indirect evidence for increased stress behavior. Taken together, these data suggest that mainly Ucn2 and Ucn3 could be involved in adrenal stress response regulation while Ucn2 additionally appears to play a role in morphology and growth of the adrenal gland.

Inflexibly Focused under Stress: Acute Psychosocial Stress Increases Shielding of Action Goals at the Expense of Reduced Cognitive Flexibility with Increasing Time Lag to the Stressor

Dynamically adjusting the right amount of goal shielding to varying situational demands is associated with the flexibility of cognitive control, typically linked with pFC functioning. Although stress hormones are found to also bind to prefrontal receptors, the link between stress and cognitive control remains elusive. Based on that, we aimed at investigating effects of acute psychosocial stress on dynamic control adjustments. Forty-eight healthy volunteers were exposed to either a well-established stress induction protocol (the Trier Social Stress Test, TSST) or a standardized control situation before a selective attention (Simon) task involving response conflicts. The individual physiological stress response was monitored by analyzing levels of free cortisol and α-amylase activity in saliva samples showing that the TSST reliably induced an increase of endogenous stress hormone levels. Acute stress did not inevitably impair cognitive functioning, however, as stressed participants showed tonically increased goal shielding (to reduce interference) at the expense of decreased cognitive flexibility. Importantly, as a novel finding in humans, stress effects on cognitive functions were not present immediately after the stress experience but developed gradually over time and, therefore, paralleled the time course of the hypothalamus-pituitary-adrenal (HPA) stress response. In addition, the total increase of individual cortisol levels reflecting HPA activity, but not the total changes in α-amylase activity associated with sympathetic activity, was reversely related to the amount of cognitive flexibility in the final block of testing. Our study provides evidence for a stress-induced time-dependent decrease of cognitive flexibility that might be related to changes in cortisol levels.

Influence of Cardiopulmonary Bypass (CPB) on Secretion of Sex Steroids in Children

Background: Cardiac surgery with cardiopulmonary Bypass (CPB) leads to increased adrenal stress response. The role of androgens like testosterone or dihydrotestosterone (DHT) in mortality of critically ill adult patients is well known. In estrogens, antiinflammatory effects via inhibition of inflammatory cytokine transcription have been described and are associated with better neurological outcome. Data on postoperative metabolism of sex steroids after cardiac surgery on CPB are rare. Aims: Does cardiac surgery with CPB lead to different sex steroids patterns in pediatric patients compared to surgery without CPB? Methods: Prospective measurement of sex steroids (testosterone, DHT, estriol, 17-beta-estradiol, 17-OH-pregnanolone, pregnanedial, pregnanetriol, 11-oxo-etiocholanolone ) in 24h urine samples before and after surgery with CPB (n=29; median age 7.6 months; 8 girls; 5 ASD, 11 VSD, 6 TOF, 7 AVSD) compared to patient who underwent surgery without CPB (n=19, 8 months; 3 girls). Results: There were no significant differences in age, weight or gender. The CPB group showed a significant increase in DHT (Wilcoxon Test; Median 12.1 [Range 0-58.5] vs 6.6 [0-39.1]; p=0.0015), estriol (2.5[0-10.5] vs 1.3 [0-11.8] p=0.0023) and 17beta-estradiol (8.0 [0-27.3] vs 0.5 [0-8.6];p< 0.0001), and a trend towards higher testosterone (4.60[0-27.82] vs 2.44[0-10.79]; p=0.0715). Progesterone metabolites (17-OH-pregnanolone, pregnanetriol and 11-oxo-pregnanetriol) showed a stronger increase in the CPB group than in controls (p=0.008; p=0.022; p=0.005, respectively). Conclusions: Cardiac surgery with CPB leads to higher secretion of androgens, estradiol and progesterone compared to surgery without CPB. These findings suggest an important role of sex steroids in pediatric cardiac surgery already in early childhood.

Adrenal Function After Pediatric Cardiac Surgery Determined by Gas Chromatography-Mass Spectrometry

Objective: To address the questions whether cardiac surgery with cardiopulmonary bypass (CPB) triggers a more intense adrenal stress response and an altered cortisol metabolism compared to surgery without CPB?

The newborn rat's stress system readily habituates to repeated and prolonged maternal separation, while continuing to respond to stressors in context dependent fashion

Adrenal corticosterone secretion of newborn mice rapidly desensitizes to repeated maternal absence. The present study investigated the effects of novelty exposure, maternal care and genotype on this phenomenon. Maternal separation (MS) took place on postnatal days ( pnd) 3–5. In Wistar rats, the degree of novelty in the MS-environment was varied by exposing pups to: (i) “home separation”: pups remained in the home cage; (ii) “novel separation”: pups were placed individually in a novel cage. Maternal care was recorded on pnd 1 to 4. To investigate the effect of genotype, we also examined Long Evans in the “home separation” condition. Basal and stress-induced ACTH and corticosterone levels were measured. Adrenal tyrosine hydroxylase (TH) and melanocortin receptor-2 (MCR-2) proteins served as markers for adrenal function. We show, in both rat strains, that the rise in plasma corticosterone induced by a single 8 h-MS on pnd 5 was abolished, when this separation procedure had also been performed on pnd 3 and 4. Habituation to maternal absence occurred irrespective of housing conditions. However, pups in the “home separation” condition received less maternal care upon reunion than those placed in the “novel separation”. These “home separation” pups appeared more responsive to a subsequent acute novelty-stressor, and their adrenal TH and MCR-2 were higher. Long Evans rats appeared more stress responsive than the Wistars, in the home separation condition. In conclusion, separation environment, maternal care and genotype do not affect adrenal desensitization to repeated 8 h-MS itself, but may modulate the adrenal stress-responsiveness of separated pups.

Mu‐opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic–pituitary–adrenal axis adrenocorticotropic hormone stress response to metyrapone

The mu-opioid receptor encoded by the gene OPRM1 plays a primary role in opiate, alcohol, cocaine and nicotine addiction. Studies using opioid antagonists demonstrate that the mu-opioid receptor (MOP-r) also mediates the hypothalamic-pituitary-adrenal (HPA) axis stress response. A common polymorphism in exon one of the MOP-r gene, A118G, has been shown to significantly alter receptor function and MOP-r gene expression; therefore, this variant likely affects HPA-axis responsivity. In the current study, we have investigated whether the presence of the 118AG variant genotype affects HPA axis responsivity to the stressor metyrapone, which transiently blocks glucocorticoid production in the adrenal cortex. Forty-eight normal and healthy volunteers (32 men, 16 women) were studied, among whom nine men and seven women had the 118AG genotype. The 118G allele blunted the adrenocorticotropic hormone (ACTH) response to metyrapone. Although there was no difference in basal levels of ACTH, subjects with the 118AG genotype had a more modest rise and resultant significantly lower ACTH levels than those with the prototype 118AA at the 8-hour time point (P < 0.02). We found no significant difference between genders. These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele.

Adrenal gland responses to lipopolysaccharide after stress and ethanol administration in male rats

All forms of stress, including restraint stress (RS) and lipopolysaccharide (LPS) administration, activate the hypothalamic–pituitary–adrenal (HPA) axis. LPS binds to a recognition protein (CD14) and toll-like receptor 2/4 in different cells and tissues, including the adrenal gland, to induce the production of cytokines and cause upregulation of cyclooxygenase and nitric oxide synthase (NOS) enzymes. Acute ethanol exposure activates the HPA axis, but in some conditions prolonged administration can dampen this activation as well as decrease the inflammatory responses to LPS. Therefore, this study was designed to evaluate the adrenal response to a challenge dose of LPS (50 μg/kg) injected i.p., after submitting male rats to RS, twice a day (2 h each time) for 5 days and/or ethanol administration (3 g/kg) by gavage also for 5 days, twice daily. At the end of the experiment, plasma corticosterone concentrations and adrenal gland content of prostaglandin E (PGE) and NOS activity were measured as stress mediators. The results showed that repetitive ethanol administration attenuated the adrenal stress response to LPS challenge alone and after RS, by preventing the increase in plasma corticosterone concentrations and by decreasing the PGE content and NOS activity in the adrenal gland. Therefore, we conclude that moderate alcohol consumption could attenuate the effects of psychophysical stress and impair an inflammatory response.

Differential mRNA expression of genes in the porcine adrenal gland associated with psychosocial stress

To gain insight into the adrenal stress response, we analysed differential mRNA expression of genes associated with psychosocial stress in the pig (Sus scrofa domestica). Various levels of psychosocial stress were induced by mixing groups of unfamiliar pigs with different aggressiveness. We selected two experimental groups for comparison, each comprising eight animals, which differed significantly in aggressive behaviour and plasma cortisol levels. To identify differentially expressed genes, we compared the adrenal transcriptome of these two groups of pigs, using the Affymetrix GeneChip porcine Genome Array. Bioinformatic analysis revealed that psychosocial stress induced upregulation of transcripts enriched for functions associated with cholesterol accumulation and downregulation of transcripts enriched for functions associated with cell growth and death. These responses are similar to those induced by ACTH stimulation. Nevertheless, the majority of the differentially expressed genes were so far not described as ACTH responsive. Some, such as GAL and GALP, may have responded to sympathoadrenal stimulation. Several of the differentially expressed transcripts, such as AGT, are associated with processes modulating steroidogenic response of adrenocortical cells to ACTH. One of the most significant findings was upregulation of LOC100039095, comprising a precursor of the microRNA miR-202, pointing to a previously unrecognised layer of regulation of adrenal steroidogenesis by microRNA. Our study, performed under entirely physiological conditions, complements previous studies focusing either on a single adrenal tissue and/or on a single stimulus, and contributes to understanding of the fine-tuning of adrenal stress response.

A Yogurt of the Future as an Anxiety Treatment

Over the past few years, research in rodents has revealed the existence of a “microbiota–gut–brain axis,” through which microbial actions are mediated through vagal afferent nerves to affect functional bowel disorders, hypothalamic–pituitary–adrenal axis stress responses, and anxiety behaviors. Now, researchers from two laboratories using slightly different …

Lipopolysaccharide directly stimulates aldosterone production via toll-like receptor 2 and toll-like receptor 4 related PI3K/Akt pathway in rat adrenal zona glomerulosa cells

The level of circulating endotoxin is related to the severity of cardiovascular disease. One of the indexes for the prognosis of cardiovascular disease is the plasma aldosterone level. Recently, the Toll-like receptors (TLRs), lipopolysaccharide (LPS)-regulated receptors, were found not only to mediate the inflammatory response but also to be important in the adrenal stress response. Whether LPS via TLRs induced aldosterone production in adrenal zona glomerulosa (ZG) cells was not clear. Our results suggest that LPS-induced aldosterone secretion in a time- and dose-dependent manner and via TLR2 and TLR4 signaling pathway. Administration of LPS can enhance steroidogenesis enzyme expression such as scavenger receptor-B1 (SR-B1), steroidogenic acute regulatory protein (StAR) and P450 side chain cleavage (P450scc) enzyme. LPS-induced SR-B1 and StAR protein expression are abolished by TLR2 blocker. Furthermore, we demonstrated that phosphorylation of Akt was elevated by LPS treatment and reduced by TLR2 blockers, TLR4 blockers, and LY294002 (PI(3)K inhibitor). Those inhibitors of PI(3)K/Akt pathways also abolish LPS-induced aldosterone secretion and SR-B1 protein level. In conclusion, LPS-induced aldosterone production and SR-B1 proteins expression are through the TLR2 and TLR4 related PI(3)K/Akt pathways in adrenal ZG cells.