Glucocorticoid Action Research Articles

Annual Research Review: Social relationships and the immune system during development.

A child's social relationships serve critical functions during development. The interface between a child's social world and their immune system, particularly innate immunity, which helped children survive in the face of infections, nutritional scarcity, and violence throughout human history, is the focus of this Annual Research Review. This article reviews the state of research on social relationships and innate immune inflammation during childhood. Warmth and rejection in childhood social relationships, as well as physical trauma and unpredictable social environments, were not consistently related to circulating inflammatory markers such as interleukin-6 and C-reactive protein during childhood. Instead, links between social environments and inflammation were observed in studies that focus on children with greater background risk factors, such as low family socioeconomic status, family history of mood disorders, or presence of chronic interpersonal stressors combined with acute episodic stressors. In addition, studies on worse childhood social environments and greater inflammation in adulthood were more consistent. Warmth and rejection in the social environment may be related to sensitivity of immune cells to the anti-inflammatory actions of glucocorticoids, though this is primarily observed in adolescent women at risk for depression. Additional mechanistic evidence suggests that greater warmth and less rejection are related to processes that regulate inflammation, including greater expression of the glucocorticoid receptor gene and lower expression of genes that are responsive to the pro-inflammatory transcription factor NF-kappa B. The article concludes by discussing implications of the interface between a child's social relationships and inflammation for mental health and other recent (on evolutionary timescales) health threats, as well as recommendations for future research, and recommendations for researchers interested in integrating inflammatory measures in developmental research.

Effects of physiological changes and social life events on adrenal glucocorticoid activity in female zoo-housed Asian elephants (Elephas maximus).

Ensuring good health and welfare is an increasingly important consideration for conservation of endangered species and includes breeding of individuals managed under human care. Understanding how factors in the captive environment affect individual animal wellbeing can be aided by long-term monitoring of biological functioning. This study involved longitudinal assessments (4 to 28 years) of reproductive and adrenal hormones in zoo-housed female Asian elephants (Elephas maximus) (age range 4 to ~71 years) to elucidate patterns in adrenal glucocorticoid (GC) activity in association with reproductive and demographic factors, and examine individual response to major social changes. Concentrations of serum and urinary cortisol covaried more consistently with physiological changes (ovarian cycle phase, puberty, pregnancy, lactational anestrus, and age) than with social life events (births, deaths, and facility transfers). Cortisol fluctuated across the ovarian cycle with mean concentrations being higher in the follicular than in the luteal phase, and concentrations were highest in lactational anestrous compared to all other reproductive states. The elephants in this study exhibited substantial individuality in adrenal GC response to major social change, reinforcing the need to assess welfare on an individual basis and to consider factors influencing the impact of perceived stressors, such as social relationships, social support, temperament, and life history. Outcomes from this study deepen our understanding of Asian elephant physiology and highlight the importance of taking intrinsic patterns of hormone secretion into account when evaluating the impact of external factors. Finally, a better understanding of the impact of social change and resiliency in response to real and perceived stressors allows us to improve social management to enhance welfare in both captive settings and free-ranging environments.

Prognostic factors in IgG4-related disease: a long-term monocentric Chinese cohort study.

Patients with IgG4-related disease (IgG4-RD) suffer high relapse rates during long-term treatment, but factors that predict relapse outcomes are not well established. In the present study, we aimed to identify predictive factors for treatment resistance and disease relapse in a Chinese IgG4-RD cohort. This study enrolled 102 patients newly diagnosed with IgG4-RD. Disease prognosis was determined by evaluating disease activity and dosage of glucocorticoids. Predictive factors for refractory and relapsed disease were identified by univariate analysis and Cox regression. Among the 102 patients, 78 cases received medical treatment with regular follow-up (21 [6-111] months). During the follow-up period, 55 (70.5%) patients sustained clinical remission, and 23 (29.5%) patients suffered refractory or relapsed disease. The relapse rate of the patients with IgG4-RD was significantly higher among patients who stopped taking medicine than among those who continued treatment with glucocorticoids (GC) + immunosuppressor (IM). Serum TNF-α ≥ 13 pg/mL, sIL-2R ≥ 1010 U/mL, total cholesterol < 3.55 mmol/L, low-density lipoprotein < 2.0 mmol/L, IgG ≥ 20.2 g/L, and drug withdrawal were predictive factors for refractory and relapsed IgG4-RD. Multivariate Cox regression revealed that both sIL-2R and TNF-α were independent risk factors for refractory and relapsed disease. The combination of GC and IM treatment was an independent protective factor against refractory and relapsed IgG4-RD. High serum levels of sIL-2R and TNF-α may be informative risk factors for refractory and relapsed IgG4-RD. Our data suggest that a combination treatment of GC along with IM may be protective against refractory and relapsed IgG4-RD. Key Points • High sIL-2R and TNF-α levels are informative risk factors for refractory and relapsed IgG4-related disease. • Combination treatment of GC with IM protects against refractory and relapsed IgG4-related disease.

Local steroid activation is a critical mediator of the anti-inflammatory actions of therapeutic glucocorticoids

ObjectivesThe enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites of inflammation, its...

Glucocorticoid-dependent transcription in skin requires epidermal expression of the glucocorticoid receptor and is modulated by the mineralocorticoid receptor

Glucocorticoid (GC) actions are mediated through two closely related ligand-dependent transcription factors, the GC receptor (GR) and the mineralocorticoid receptor (MR). Given the wide and effective use of GCs to combat skin inflammatory diseases, it is important to understand the relative contribution of these receptors to the transcriptional response to topical GCs. We evaluated the gene expression profiles in the skin of mice with epidermal-specific loss of GR (GREKO), MR (MREKO), or both (double KO; DKO) in response to dexamethasone (Dex). The overall transcriptional response was abolished in GREKO and DKO skin suggesting dependence of the underlying dermis on the presence of epidermal GR. Indeed, the observed dermal GC resistance correlated with a constitutive decrease in GR activity and up-regulation of p38 activity in this skin compartment. Upon Dex treatment, more than 90% of differentially expressed genes (DEGs) in CO overlapped with MREKO. However, the number of DEGs was fourfold increased and the magnitude of response was higher in MREKO vs CO, affecting both gene induction and repression. Taken together our data reveal that, in the cutaneous transcriptional response to GCs mediated through endogenous receptors, epidermal GR is mandatory while epidermal MR acts as a chief modulator of gene expression.

Cortisol Circadian Rhythm and Insulin Resistance in Muscle: Effect of Dosing and Timing of Hydrocortisone Exposure on Insulin Sensitivity in Synchronized Muscle Cells

Introduction/Aim: Circadian clock disruption is emerging as a risk factor for metabolic disorders, and particularly, alterations in clock genes circadian expression have been shown to influence insulin sensitivity. Recently, the reciprocal interplay between the circadian clock machinery and hypothal­amus-pituitary-adrenal axis has been largely demonstrated: the circadian clock may control the physiological circadian endogenous glucocorticoid (GC) secretion and action; GCs, in turn, are potent regulators of the circadian clock and their inappropriate replacement has been associated with metabolic impairment. The aim of the current study was to investigate in vitro the interaction between the timing-of-the-day exposure to different hydrocortisone (HC) concentrations and muscle insulin sensitivity. Methods: Serum-shock synchronized mouse skeletal muscle C2C12 cells were exposed to different HC concentrations resembling the circulating daily physiological cortisol profile (standard cortisol profile) and the circulating daily cortisol profile that reached in adrenal insufficient (AI) patients treated with once-daily modified-release HC (flat cortisol profile) and treated with thrice-daily conventional immediate-release HC (steep cortisol profile). The 24 h spontaneous oscillation of the clock genes in synchronized C2C12 cells was used to align the timing for in vitro HC exposure (Bmal1 acrophase, midphase, and bathyphase) with the reference times of cortisol peaks in AI patients treated with IR-HC (8 a.m., 1 p.m., and 6 p.m.). A panel of 84 insulin sensitivity-related genes and intracellular insulin signaling proteins were analyzed by RT-qPCR and Western blot, respectively. Results: The steep profile, characterized by a higher HC exposure during Bmal1bathyphase, produced significant downregulation in 21 insulin sensitivity-related genes including Insr, Irs1, Irs2, Pi3kca, and Adipor2, compared to the flat and standard profile. Reduced intracellular IRS1 Tyr608, AKT Ser473, AMPK Thr172, and ACC Ser79 phosphorylations were also observed. Conclusions: The current study demonstrated that late-in-the-day cortisol exposure modulates insulin sensitivity-related gene expression and intracellular insulin signaling in skeletal muscle cells.

Glucocorticoid Activation of Anti-Inflammatory Macrophages in Coordination with STAT6 Protects Against Insulin Resistance and Maintains Homeothermy

Obesity and insulin resistance are a global health problem and directly linked to macrophage-driven inflammation of the adipose tissue. Glucocorticoid (GC) therapy, widely used to treat inflammatory conditions, is associated with metabolic side effects, including adiposity and insulin resistance. It is unknown however, whether anti-inflammatory actions of glucocorticoids at physiological levels can have beneficial effects on adipose tissue inflammation. We hypothesized that GCs may limit insulin resistance by acting on immune cells. By deletion of the GC receptor (GR) in macrophages in mice, we show that GC signaling in macrophages protects against obesity-related insulin resistance, by limiting adipose tissue inflammation. Consequently, the reduction of anti-inflammatory macrophages leads to diminished maintenance of body temperature during cold exposure and endotoxin shock, linking GC action in macrophages to homeothermy. Mechanistically, Macrophages deficient for GR are unable to fully develop into an anti-inflammatory phenotype and are refractory to IL-4 signaling, due to reduced STAT6 DNA loading. Our results demonstrate that GCs play an important homeostatic role in macrophages during obesity by limiting adipose tissue inflammation and promoting insulin sensitivity. We also identify a cooperation of GC signaling with STAT6 in macrophages to promote alternative activation, in turn assisting in homeothermy.

Cortisol rapidly stimulates calcium waves in the developing trunk muscle of zebrafish

Glucocorticoids (GCs) play a role in stress coping by activating the glucocorticoid receptor (GR), a ligand-bound transcription factor. GCs also exert rapid effects that are nongenomic by modulating second messenger signaling, including Ca2+. However, the mechanism of action of GCs in modulating cytoplasmic free calcium level ([Ca2+]i) is unclear. We hypothesized that cortisol increases ([Ca2+]i) in zebrafish (Danio rerio) muscle, and this is independent of GR activation. Indeed, cortisol rapidly stimulated ([Ca2+]i) rise in the developing trunk muscle (DTM), and this response was not abolished in the GR knockout zebrafish. The rapid cortisol-induced ([Ca2+]i) rise was reduced with EGTA, and completely abolished by the pharmacological inhibition of the calcium release-activated calcium channel (CRACC). Also, cortisol stimulation rapidly increased the expression of Orai1, the pore forming protein subunit of CRACC, in the DTM. Altogether, rapid nongenomic action of cortisol on muscle function may involve Ca2+ signaling by CRACC gating in zebrafish.

Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy.

Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences including adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.

Pharmacodynamic mechanisms of anti-inflammatory drugs on the chemosensitization of multidrug-resistant cancers and the pharmacogenetics effectiveness.

Drug resistance as a remarkable issue in cancer treatment is associated with inflammation which occurs through complex chemical reactions in the tumor microenvironment. Recent studies have implicated that glucocorticoids and NSAIDs are mainly useful combinations for inflammatory response modulation in chemotherapeutic protocols for cancer treatment. Immunosuppressive actions of glucocorticoids and NSAIDs are mainly mediated by the transrepression or activation regulation of inflammatory genes with different DNA-bound transcription factors including AP-1, NFAT, NF-κB, STAT and also, varying functions of COX enzymes in cancer cells. Interestingly, many investigations have proved the benefits of these anti-inflammatory agents in the quenching of multidrug resistance pathways. Numerous analyses on the ABC transporter promoters showed conserved nucleotide sequences with several DNA response elements that participate in transcriptional regulation. Furthermore, genetic variations in nucleotide sequences of membrane transporters were strongly associated with changes in these transporters' expression or function and a substantial impact on systemic drug exposure and toxicity. It appeared that several polymorphisms in MDR transporter genes especially MDR1 have influenced the regulatory mechanisms and explained differences in glucocorticoid responses.

Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice

ObjectiveAging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging. MethodsMice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus STAT3 phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured. ResultsAs they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2OB/OCY-tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic STAT3, from 6 months of age onwards. In contrast, HSD2OB/OCY-tg mice remained leptin-sensitive throughout the study. Compared to HSD2OB/OCY-tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2OB/OCY-tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2OB/OCY-tg mice, compared to wild-type mice. ConclusionsSkeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.

Insuficiencia suprarrenal

Adrenal insufficiency (AI) is a low-incidence disorder with high comorbidity; it is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in adrenal androgens and/or mineralocorticoids, resulting from disease intrinsic to the adrenal cortex (primary AI), pituitary impairment (secondary AI) or hypothalamic disease (tertiary AI). Symptomatology varies widely depending on impairment level and deficit acuteness. Nevertheless, diagnosis requires a high suspicion level, depending entirely on the demonstration that hormonal secretion is inappropriately low using hormonal tests. Treatment goal is glucocorticoid and hormonal replacement avoiding deleterious effects caused by an excessive dosage. Hydrocortisone and fludrocortisone are the glucocorticoid and mineralocorticoid of choice, respectively. Hormone replacement screening is mainly clinical. Patients should be informed of dose adjustments in intercurrent situations. In adrenal crisis treatment has to be initiated as sooner as possible (intravenous glucocorticoid and electrolyte replacement).

Acute kidney injury after brain injury: does it exist?

Acute kidney injury (AKI) is frequent after cerebral insults, with an incidence close to 10% in both traumatic brain injury (TBI) and cerebrovascular disease. AKI in this context has substantial impact on mortality and neurological outcome. Numerous factors may play a role in the development of AKI after brain injury: intravascular volume depletion, raised-intra-abdominal pressure, rhabdomyolysis or sepsis in TBI; age, ischemic heart disease or arteriosclerotic disease in stroke. However, brain-kidney crosstalk mechanisms are complex and there remains a strong rationale for a causal relationship between brain and kidney injury. Cerebral lesions might alter renal function through a neuro-endocrine pathway combining sympathetic system, renin-angiotensin-aldosterone and glucocorticoid activation. Altogether these systems impair renal autoregulation ultimately leading to AKI. In addition, cerebral lesions might lead to a systemic inflammatory response making the kidney vulnerable for dysfunction. Indeed, inflammation and immune system activation are core mechanisms for the development of AKI. Last, direct lesions of specific area of the brain might lead to vasomotor changes and AKI. In this work, we reviewed the epidemiology of AKI after brain injury and examine potential mechanisms suggesting a causal relationship between these two entities.

Liver at the nexus of rat postnatal HPA axis maturation and sexual dimorphism.

Normal function of the hypothalamic-pituitary-adrenal (HPA) axis is critical for survival, and its development is choreographed for age-, sex- and context-specific actions. The liver influences HPA ontogeny, integrating diverse endocrine signals that inhibit or activate its development. This review examines how developmental changes in the expression of genes in the liver coordinate postnatal changes in multiple endocrine systems that facilitate the maturation and sexual dimorphism of the rat HPA axis. Specifically, it examines how the ontogeny of testicular androgen production, somatostatin-growth hormone activities, and hypothalamic-pituitary-thyroid axis activity intersect to influence the hepatic gene expression of insulin-like growth factor 1, corticosteroid-binding globulin, thyroxine-binding globulin, 11β-hydroxysteroid dehydrogenase type 1 and 5α-reductase type 1. The timing of such molecular changes vary between mammalian species, but they are evolutionarily conserved and are poised to control homeostasis broadly, especially during adversity. Importantly, with the liver as their nexus, these diverse endocrine systems establish the fundamental organization of the HPA axis throughout postnatal development, and thereby ultimately determine the actions of glucocorticoids during adulthood.

Phthalate esters and dexamethasone synergistically activate glucocorticoid receptor

This study was conducted to determine the endocrine-disrupting effects of phthalate esters (PAEs) on the glucocorticoid receptor (GR) signaling. Potential (anti)glucocorticoid activities of six typical PAEs including di (2-ethylhexyl) phthalate (DEHP), diisononyl phthalate (DINP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), diethyl phthalate (DEP) and dimethyl phthalate (DMP) were evaluated on human GR using cell viability assessment, reporter gene expression analysis, mRNA analysis, and molecular docking and simulation. For all tested chemicals, co-treatment of DEHP and DINP with dexamethasone (DEX) exhibited a synergistic effect on GR transactivity in the reporter assays. Such co-treatment also synergistically enhanced DEX-induced upregulation of GR mediated gene (PEPCK, FAS and MKP-1) mRNA expression in HepG2 cells and A549 cells. Molecular docking and dynamics simulations showed that hydrophobic interactions may stabilize the binding between molecules and GR. In summary, DEHP and DINP may be involved in synergistic effects via human GR, which highlight the potential endocrine-disrupting activities of PAEs as contaminants.

Using bioanalytical tools to detect and track organic micropollutants in the Ganga River near two major cities

Major rivers in India are subject to ongoing impacts from urban drain discharges, most of which contain high levels of domestic and industrial wastewater and stormwater. The aim of the present study was to determine the levels of bioactive organic micropollutants at the discharge points of major urban drains in comparison to upstream and downstream sites. To achieve this, we employed a panel of in vitro bioanalytical tools to quantify estrogenic, androgenic, progestogenic, glucocorticoid and peroxisome proliferator-like activity in water extracts collected from two Indian cities in the Ganga Basin. Cytotoxicity of the water extracts in a human-derived cell line and the potential to cause oxidative stress in a fish cell line were also investigated. We found high levels of activity for all endpoints in samples directly receiving urban drain discharge and low levels at sites upstream from drain discharges. Estrogenicity was detected at levels equivalent to 10 ng/L 17β-estradiol, representing a high likelihood of biomarker effects in fish. Sites located downstream from drain discharges exhibited low to intermediate activity in all assays. This study demonstrates the importance of managing urban drain discharges and the utility of applying bioanalytical tools to assess water quality.

Differing physiological and behavioral responses to anthropogenic factors between resident and non-resident African elephants at Mpala Ranch, Laikipia County, Kenya.

BackgroundHeterogeneous landscapes like those of Laikipia County, Kenya consist of a mosaic of land-use types, which may exert differential physiological effects on elephants that occupy and traverse them. Understanding behavioral and physiological states of wild African elephants in response to the challenges of living in human-dominated landscapes is therefore important for conservation managers to evaluate risks imposed by elephants to humans and vice versa. Several conservation physiology tools have been developed to assess how animals respond to both natural and anthropogenic changes, and determine biological impacts. This study investigated how migratory and avoidance behavioral to vehicle presence, and vegetation quality affected fecal glucocorticoid (GC) metabolite (FGM) concentrations in African elephants at Mpala Ranch, Laikipia County, Kenya.MethodsThe study compared adrenal glucocorticoid activity of resident elephants that live within Mpala (n = 57) and non-resident elephants whose space use patterns overlap several ranches (n = 99) in Laikipia County, Kenya. Fecal samples were collected for a 4-month period between April and August for analysis of FGM concentrations. Behavioral reactions to research vehicles and body condition also were assessed. Satellite images from Terra Moderate Resolution Imaging (MODIS MOD13Q1) were downloaded and processed using Google Earth Engine to calculate a Normalized Difference Vegetation Index (NDVI) as a measure of vegetation quality.ResultsAs expected, there was a positive correlation between avoidance behavior to vehicle presence and FGM concentrations in both resident and non-resident elephants, whereas there was an inverse relationship between FGM concentrations and NDVI values. Our study also found a positive influence of age on the FGM concentrations, but there were no relationships between FGM and sex, social group type, herd size, and body condition. However, contrary to our expectations, resident elephants had higher FGM concentrations than non-residents.DiscussionFindings reveal elephants with stronger avoidance responses to research vehicles and resident elephants with relatively smaller home ranges exhibited higher FGM concentrations within the Mpala Ranch, Kenya and surrounding areas. Higher vegetative quality within the ranges occupied by non-resident elephants in Laikipia may be one reason for lower FGM, and an indication that the non-residents are tracking better forage quality to improve energy balance and reduce overall GC output. Additionally, our study found a positive influence of age, but no other demographic variables on FGM concentrations. Finally, adrenal glucocorticoid activity was inversely related to vegetative quality. Our findings can help conservation managers better understand how behavior and environment influences the physiological states of African elephants, and how management intervention might mitigate negative human–elephant interactions.

Contribution of placental 11β-HSD2 to the pathogenesis of preeclampsia.

Preeclampsia, a major human pregnancy-specific disorder, leads to maternal and fetal morbidity and mortality. Here we reported that 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), an enzyme that degrades active glucocorticoids, is one of the key factors that contributes to preeclampsia development. In the pregnant rat model, we firstly confirmed that administration of 11β-HSD2 inhibitor carbenoxolone (CBX) subcutaneously or by placenta-targeted delivery system could lead to a decrease in placental 11β-HSD2 expression and activity and an increase in corticosterone level in placenta and maternal circulation. Then, we showed that subcutaneous administration and placenta-targeted delivery of CBX resulted in the hallmark of preeclampsia-like features including hypertension, proteinuria, renal damages as well as elevated circulatory soluble fms-like tyrosine kinase 1 (sFlt1) and increased sFlt1/placental growth factor (PlGF) ratio in pregnant rats. These animals displayed decreased trophoblast invasion in uterus, impaired spiral artery remodeling, and reduced placental blood flow. Preeclampsia-like features could also be induced by administration of dexamethasone in pregnant rats. In the cultured human trophoblast models, we found that cortisol only inhibited migration and invasion of the extravillous trophoblasts with 11β-HSD2 knockdown, and promoted sFlt1 release in the cultured syncytiotrophoblasts with 11β-HSD2 knockdown. Furthermore, we elucidated that cortisol stimulated a disintegrin and metalloprotease (ADAM)17 expression in placentas, thereby promoting sFlt1 release in placenta. Collectively, our study provided the evidence that placental 11β-HSD2 dysfunction plays a key role in the development of preeclampsia and immediately identified innovative target to counteract preeclampsia.

Stress-induced alterations of social behavior are reversible by antagonism of steroid hormones in C57/BL6 mice

Various disturbances of social behavior, such as autism, depression, or posttraumatic stress disorder, have been associated with an altered steroid hormone homeostasis and a dysregulation of the hypothalamus–pituitary–adrenal axis. A link between steroid hormone antagonists and the treatment of stress-related conditions has been suggested. We evaluated the effects of stress induction on social behavior in the three chambers and its potential reversibility upon specific steroid hormone antagonism in mice. C57BL/6 mice were stressed twice daily for 8 days by chronic swim testing. Social behavior was evaluated by measuring, first, the preference for sociability and, second, the preference for social novelty in the three-chamber approach before and after the chronic swim test. The reversibility of behavior upon stress induction was analyzed after applying steroid hormone antagonists targeting glucocorticoids with etomidate, mineralocorticoids with potassium canrenoate, and androgens with cyproterone acetate and metformin. In the chronic swim test, increased floating time from 0.8 ± 0.2 min up to 4.8 ± 0.25 min was detected (p < 0.01). In the three-chamber approach, increased preference for sociability and decreased preference for social novelty was detected pre- versus post-stress induction. These alterations of social behavior were barely affected by etomidate and potassium canrenoate, whereas the two androgen antagonists metformin and cyproterone acetate restored social behavior even beyond baseline conditions. The alteration of social behavior was better reversed by the androgen as compared with the glucocorticoid and mineralocorticoid antagonists. This suggests that social behavior is primarily controlled by androgen rather than by glucocorticoid or mineralocorticoid action. The stress-induced changes in preference for sociability are incompletely explained by steroid hormone action alone. As the best response was related to metformin, an effect via glucose levels might confound the results and should be subject to future research.

Abstract MP25: Expression Of Urinary Somatic And Soluble N-domain Isoforms Of Angiotensin Converting Enzyme And Association With Different Nutritional Status And Cardiovascular Risk Profile

Angiotensin converting enzyme (ACE) plays a dominant role in renal and cardiovascular diseases, obesity and diabetes. The somatic ACE (130-190 kDa) is composed of two homologous N- and C- domains. Two soluble N-domain isoforms have been described in human urine with 65 and 90KDa. Studies have supported that N-domain ACE with 90KDa is a biomarker for hypertension, pre-eclampsia and inflammation. We analyzed the expression of somatic and soluble N-domain ACE isoforms in urine of children and adolescents with different nutritional status and cardiovascular risk profile. The volunteers aged from 6 to 19 years were classified into four groups according to their BMI percentile; underweight (n=51), normal weight (n = 53), overweight (n=53) and obese (n=49). Waist-height-ratio (WHtR) was used to assess cardiovascular risk profile dividing the participants into normal risk (n=105) and high risk (n=101). The urines were concentrated 10-fold and dialyzed with Tris-HCl pH 8 and pure water. Then, we performed western blot analysis using 50μg of lyophilized urinary protein, using the ACE polyclonal antibody Y1. Protein detection was performed by chemiluminescent and analysis in Image Lab software utilizing total protein stain for normalization. ACE expression is augmented in obese children when compared with normal weight children ( 0.09 vs 0.53 arbitrary units, p=0,04 ). The higher cardiovascular risk group also presented increased expression of ACE ( 0.27 vs 0.09 arbitrary units, p=0.046 ). The 90KDa N-domain isoform is frequently found in the high cardiovascular risk children ( p= 0.02 ). According to Spearman correlation test, the expression of 90 kDa N-domain ACE correlates positively with waist circumference, WHtR, BMI percentile and Z-score of BMI. Increased ACE expression in obese children contributes to higher cardiovascular risk once this enzyme biosynthesizes Angiotensin II which promotes blood pressure increase, sympathetic nervous system activation and release of glucocorticoids from adrenal gland. ACE expression is also augmented in children with high cardiovascular risk. Presence of 90 KDa N-domain ACE in urine of children and adolescents is a biomarker of poor prognostic for cardiovascular disease in childhood obesity.