Browsing by Author "Tapia-Castillo, Alejandra"

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    Classic and nonclassic apparent mineralocorticoid excess syndrome
    (Endocrine Society, 2020) Carvajal, Cristián A.; Tapia-Castillo, Alejandra; Vecchiola, Andrea; Baudrand, Rene; Fardella, Carlos
    © 2020 Endocrine Society. All rights reserved.Context: Arterial hypertension (AHT) is one of the most frequent pathologies in the general population. Subtypes of essential hypertension characterized by low renin levels allowed the identification of 2 different clinical entities: aldosterone-mediated mineralocorticoid receptor (MR) activation and cortisol-mediated MR activation. Evidence Acquisition: This review is based upon a search of Pubmed and Google Scholar databases, up to August 2019, for all publications relating to endocrine hypertension, apparent mineralocorticoid excess (AME) and cortisol (F) to cortisone (E) metabolism. Evidence Synthesis: The spectrum of cortisol-mediated MR activation includes the classic AME syndrome to milder (nonclassic) forms of AME, the latter with a much higher prevalence (7.1%) than classic AME but different phenotype and genotype. Nonclassic AME (NC-AME) is mainly related to partial 11βHSD2 deficiency associated with genetic variations and epigenetic modifications (first hit) and potential additive actions of endogenous or exogenous inhibitors (ie, glycyrrhetinic acid-like factors [GALFS]) and other factors (ie, age, high sodium intake) (second hit). Subjects with NC-AME are characterized by a high F/E ratio, low E levels, normal to elevated blood pressure, low plasma renin and increased urinary potassium excretion. NCAME condition should benefit from low-sodium and potassium diet recommendations and monotherapy with MR antagonists. Conclusion: NC-AME has a higher prevalence and a milder phenotypical spectrum than AME. NC-AME etiology is associated to a first hit (gene and epigene level) and an additive second hit. NC-AME subjects are candidates to be treated with MR antagonists aimed to improve blood pressure, end-organ damage, and modulate the renin levels.
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    Cortisol resistance in the degu (Octodon degus)
    (2022) Yao, Yi-Zhou; Brennan, Francine E.; Carvajal, Cristian A.; Vecchiola, Andrea; Tapia-Castillo, Alejandra; Fardella, Carlos E.; Fuller, Peter J.
    Cortisol resistance has also been reported in the degu, Octodon degus, a New World hystricomorph endemic to central Chile. The degu is used as a model for studies of stress and diurnal rhythms, parental behaviour and female masculinization. Another New World hystricomorph, the guinea pig, also exhibits glucocorticoid resistance, a result of amino acid sequences that differ from other mammalian glucocorticoid receptors (GR). Mutations in the ligand-binding domain of the human GR have been identified in familial or sporadic generalised cortisol resistance as have variants in the guinea pig. To address the possibility that the high levels of cortisol observed in the degu are a result of the same or similar sequence variations observed in the guinea pig GR, we have cloned, expressed and characterised the ligand-binding domain (LBD) of the degu GR. Somewhat unexpectedly, neither the amino acids nor the region involved in the resistance observed in the guinea pig GR are relevant in the degu GR. The relative resistance to cortisol observed in the degu GR is conferred by the substitution of two isoleucine residues, which are highly conserved in the GR across species, with a valine doublet. These amino acids lie in the region between helices 5 and 6 of the GR LBD, a region known to be important in determining the affinity of ligand-binding in steroid receptors.
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    Plasminogen Activator Inhibitor-1 and Adiponectin Are Associated With Metabolic Syndrome Components
    (2022) Vecchiola, Andrea; Garcia, Killen; Gonzalez-Gomez, Luis M.; Tapia-Castillo, Alejandra; Artigas, Rocio; Baudrand, Rene; Kalergis, Alexis M.; Carvajal, Cristian A.; Fardella, Carlos E.
    BACKGROUND We aimed to study the associations of adipocytokines, endothelial damage markers, and high-sensitivity C-reactive protein (hs-CRP) with metabolic syndrome (MetS) components. METHODS This cross-sectional study included 202 subjects categorized into MetS and No-MetS according to Harmonizing Adult Treatment Panel III. RESULTS Subjects with MetS showed higher levels of proinflammatory molecules but significantly lower adiponectin levels than subjects with No-MetS. Among the studied adipocytokines, plasminogen activator inhibitor-1 (PAI-1) and adiponectin showed the strongest associations with most MetS components. PAI-1 was associated with MetS (odds ratio (OR) 1.107 (1.065-1.151), P < 0.0001), whereas adiponectin was inversely associated with MetS (OR 0.710 (0.610-0.825), P < 0.0001). Following adjustment by sex, age, body mass index, and 24-hour urinary sodium excretion in a multivariate analysis, the association of PAI-1 (OR 1.090 (1.044-1.137), P < 0.0001) and adiponectin (OR 0.634 (0.519-0.775), P < 0.0001) with MetS remained significant. Multivariate analyses supported a model in which systolic blood pressure (BP) could be predicted by PAI-1, hs-CRP, and matrix metalloproteinase 2 (R-2 = 0.125; P = 0.04); diastolic BP (R-2 = 0.218; P = 0.0001) and glucose (R-2 = 0.074; P = 0.0001) could be predicted by PAI-1; waist circumference could be predicted by PAI-1 and hs-CRP (R-2 = 0.28; P = 0.016). Receiver operating characteristic curve analysis showed that a PAI-1 concentration had the best sensitivity and specificity for discriminating subjects with MetS. CONCLUSION PAI-1 and adiponectin rendered the most robust associations with MetS components in a general population, indicating that unfavorable adipose tissue performance is a key contributor to these metabolic anomalies. Further prospective analyses should allow establishing whether these adipocytokines can anticipate the progress of MetS and cardiovascular risk.
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    Proteomic Profile of Urinary Extracellular Vesicles Identifies AGP1 as a Potential Biomarker of Primary Aldosteronism
    (2021) Barros, Eric R.; Rigalli, Juan Pablo; Tapia-Castillo, Alejandra; Vecchiola, Andrea; Young, Morag J.; Hoenderop, Joost G. J.; Bindels, Rene J. M.; Fardella, Carlos E.; Carvajal, Cristian A.
    Context: Primary aldosteronism (PA) represents 6% to 10% of all essential hypertension patients and is diagnosed using the aldosterone-to-renin ratio (ARR) and confirmatory studies. The complexity of PA diagnosis encourages the identification of novel PA biomarkers. Urinary extracellular vesicles (uEVs) are a potential source of biomarkers, considering that their cargo reflects the content of the parent cell.
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    Testosterona inhibe la actividad de la aldosterona sintasa silvestre y quimérica in vitro
    (Sociedad Medica de Santiago, 2021) Vecchiola Cardenas, Andrea Paola; Saldias Fuentes, Cristóbal Abraham; Carvajal Maldonado, Cristian Andrés; Campino Johnson, María Del Carmen; Allende Sanzana, Fidel Alejandro; Tapia-Castillo, Alejandra; Lagos, Carlos F.; Fardella Bello, Carlos Enrique
    © 2021 Sociedad Medica de Santiago. All rights reserved.Background: Familial hyperaldosteronism type I is caused by the generation of a chimeric aldosterone synthase enzyme (ASCE) which is regulated by ACTH instead of angiotensin II. We have reported that in vitro, the wild-type (ASWT) and chimeric aldosterone synthase (ASCE) enzymes are inhibited by progesterone and estradiol does not affect their activity. Aim: To explore the direct action of testosterone on ASWT and ASCE enzymes. Material and Methods: HEK-293 cells were transiently transfected with vectors containing the full ASWT or ASCE cDNAs. The effect of testosterone on AS enzyme activities was evaluated incubating HEK-cells transfected with enzyme vectors and adding deoxycorticosterone (DOC) alone or DOC plus increasing doses of testosterone. Aldosterone production was measured by HPLC-MS/MS. Docking of testosterone within the active sites of both enzymes was performed by modelling in silico. Results: In this system, testosterone inhibited ASWT (90% inhibition at five µM, 50% inhibitory concentration (IC50) =1.690 µM) with higher efficacy and potency than ASCE (80% inhibition at five µM, IC50=3.176 µM). Molecular modelling studies showed different orientation of testosterone in ASWT and ASCE crystal structures. Conclusions: The inhibitory effect of testosterone on ASWT or ASCE enzymes is a novel non-genomic testosterone action, suggesting that further clinical studies are needed to assess the role of testosterone in the screening and diagnosis of primary aldosteronism.