Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS) imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage.

Familial hyperaldosteronism type I (FH-I) is caused by the unequal recombination between the 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, resulting in the generation of a CYP11B1/B2 chimeric gene and abnormal adrenal aldosterone production. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Aldosterone levels rise during pregnancy, yet in pregnant women with FH-1, their hypertensive condition either remains unchanged or may even improve. The purpose of this study was to investigate in vitro whether female sex steroids modulate the activity of chimeric (ASCE) or wild type (ASWT) aldosterone synthase enzymes.

Arterial hypertension is a major health problem affecting 1.13 billion people worldwide, of which 10% could be due to endocrine pathologies related to the mineralocorticoid receptor (MR) (i.e. primary aldosteronism, 11β-hydroxysteroid dehydrogenase type 2 enzyme (HSD11B2) deficiency). The MR pathway is expressed mainly in placenta, kidney and colon epithelial cells. Current research highlights potential epigenetic regulatory mechanisms for the MR pathway. Here, specific miRNAs are being studied as epigenetic regulators, either present in cells or exosomes (nanovesicles of 40–150 nm diameter) carrying miRNA, RNA, lipids and proteins. Those miRNAs could dynamically influence the onset and progression of the mineralocorticoid arterial hypertension (AH). Aim: To isolate exosomes from polarized epithelial cells and to identify in their cargo miRNAs affecting HSD11B2 and MR gene expression. Methods: The bioinformatic tool mirWalk2.0 was used to determine miRNAs capable to interact with HSD11B2 and MR RNAs. The cell line derived from colon epithelia (Caco-2) cells was cultured and polarized in Transwells. MR pathway genes and miRNAs targeting the MR and HDS11B2 were measured by qPCR. Exosomes from apical and basolateral culture medium were isolated at 24 h of incubation in basal conditions, quantified with NanoSight-NS300 and their specific miRNA content was determined. Results: We identified bioinformatically that miRNA 135b, 644a and miRNA 488, 1205 could interact with the MR and HSD11B2, respectively. Caco-2 cells polarize after 21 days of culture (trans-epithelial resistance (TEER): 114.18 cm²), expressing polarization genes (SLC11A2, SLGT1, ALPI), genes associated to MR pathway (NR3C2, HSD11B2, SCNN1A, SLC12A2, SGK1, ATP1A1) and pre-miRNAs (135b, 644a, 488, 1205). We identified that Caco-2 release 21×109±0.69×109 (apical) and 4.1×109±0.0029×109 (basolateral) extracellular vesicles per ml of which a 36.8 and 38.5% are exosomes with a modal range in 124–125 nm diameter respectively. Preliminary results show expression of miRNA 135b, 644a, 488 and 1205 in apical and basolateral exosomes. Conclusion: Caco-2 cells release five-times more exosomes in the apical than basolateral side, both carrying miRNAs that could interact HSD11B2 and MR gene.

Introduction: The prevalence of hypertension in children and adolescent who were extremely preterm newborns (EP; ≤32 gestational weeks) has been found to be higher than in those born at term. The causes have not been well characterized. Studies support that adrenal dysregulation might be a consequence of prematurity. Objectives: To determinate if children who were EP had higher adrenal hormones and vascular remodeling biomarker than term newborn (≥38 gestational weeks). Design, subjects and methods: A pilot – cross sectional study was design. Children from the community were invited (n=235, range 5.1–15.5 years old); twelve were EP (gestational age between 30 and 32 weeks) and 223 were born at term (gestational age between 38 and 40 weeks). Anthropometric characteristics and aldosterone, plasma renin activity (PRA), aldosterone/PRA ratio (ARR), cortisol and cortisone were measured. Metalloproteinasa 2 (MMP-2) activity was measured as a vascular remodeling biomarker. Results (median): Both groups were comparables in age (10.2 vs 11.6 years; P=0.075), BMI-SDS (1.13 vs 1.18; P=0.434), height-SDS (0.48 vs 0.23; P=0.434) and blood pressure corrected by gender, age and height (systolic index 1.09 vs 1.06, P=0.184 and diastolic index 1.11 vs 1.10 P=0.797). EP newborn vs term newborn showed similar aldosterone (ng/dl): 7.6 vs 6.2 (P=0.439) and PRA (ng/ml per h): 2.16 vs 2.3 (P=0.779) but higher ARR (3.9 vs 2.6 P=0.039) and higher MMP-2 activity (Arbitrary units): 1.88 vs 1.50 (P=0.009). No statistical differences in cortisol, cortisone and cortisol/cortisone ratio were observed. Conclusions: This pilot study showed that children who were extremely preterm newborn have higher ARR and vascular remodeling than children born at term, despite similar blood pressure. Future studies to assess the importance of these findings in early prevention of hypertension are warranted.

Nontumoral cortisol dysregulation in obese individuals is associated with many facets of metabolic syndrome, including central adiposity, diabetes mellitus (T2DM), dyslipidemia, and hypertension. Glucocorticoid availability and function at the cell/tissue level are classically regulated by 11-beta hydroxysteroid dehydrogenase type (11β-HSD) enzymes. The 11β-HSD1 enzyme is expressed primarily in the liver and adipose tissue (AT) where cortisone in converted into its active form, cortisol. 11β-HSD1 expression in AT promotes adipocyte proliferation and hypertension, leading to the development of abdominal obesity and comorbidities. The 11β-HSD1 enzyme is a key therapeutic target for modulating obesity and associated metabolic disorders.In response to this need, our research aimed to design and characterize a family of nonsteroidal compounds displaying specific and selective inhibition of the 11β-HSD1 enzyme. For this purpose, we designed, synthetized, and characterized a family of adamantyloxadiazole compounds to selectively inhibit the human 11β-HSD1 enzyme that are henceforth designated sequentially from A to N (14 compounds). Our newly synthesized compounds were designed in silico and synthesized via retrosynthesis. We tested the following properties of our novel compounds: (1) their biopharmaceutical properties, (2) their inhibitory potency (IC50) over 11β-HSD1 reductase activity in cell-free assays, and (3) their relative inhibitory potency and IC50 in human adipocytes.Biopharmaceutical characterization of the compounds revealed high transcellular permeability and no interaction with P-glycoprotein, a known efflux pump that decreases oral systemic and central exposure, for Compounds J and L . In vitro studies of the inhibition of the 11β-HSD1 enzyme via cell-free and microsome-based assays indicated significant inhibitory potency, with optimal specificity and selectivity observed at the nanomolar level, highlighting both the IC50 values of Compound J (11,8 nM) and Compound L (3,9 nM), which also preserve 11b-HSD oxidase activities (> 90%). In human adipocytes, 1 µM Compounds E , J and L demonstrated a high potency of 11β-HSD1 inhibition, near 40–60%, compared to 1 µM inhibitor carbenoxolone, which showed approximately a 90% inhibition.The preclinical evaluation of these adamantyloxadiazole derivatives revealed their potential as effective inhibitors of the 11β-HSD1 enzyme, with Compounds E , J and L showing particularly relevant performance in vitro . These findings support the progression of in vivo studies to further explore their therapeutic potential in treating obesity and associated metabolic disorders.