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Ítem Adipocyte extracellular vesicles (AdEVs) promote a proinflammatory and profibrotic profile in human renal and endothelial cells in vitro(Springer Nature, 2026-02-23) Carrión, Pablo; Hernández, María Paz; Pérez, Jorge A.; Tapia-Castillo, Alejandra; Vecchiola, Andrea; Sandoval-Bórquez, Alejandra; Baudrand, René F.; Fardella, Carlos E.; Carvajal, Cristian A.OBJECTIVES: In obesity, white adipose tissue (WAT) undergoes hypertrophic and hyperplastic changes that are driven by phenotypical changes in preadipocytes and adipocytes. WAT also causes a chronic inflammatory state that modifies gene expression and the secretome, including the shedding of adipose-derived extracellular vesicles (AdEVs) into the circulation, which may influence distant cell types and modulate their phenotypes. AIM: To evaluate the effects of AdEVs on renal and endothelial cells and determine their impact on gene expression related to inflammation, fibrosis, and endothelial function. METHODS: Human SW872 preadipocytes were differentiated into adipocytes and subsequently characterized. AdEVs were isolated by ultracentrifugation and analyzed according to ISEV guidelines. Recipient human renal (HCD) and endothelial (EA.hy926) cells were exposed to AdEVs for 24 hours. Gene expression of adipokines, cytokines (IL-6, IL-1B), fibrosis markers, neutrophil gelatinaseassociated lipocalin (NGAL), and eNOS was assessed by RT-qPCR and western blotting. RESULTS: Differentiated SW872 cells displayed typical adipocyte morphology and accumulated abundant lipid droplets. Isolated AdEVs showed a donut-like morphology, characteristic size distribution, and expression of CD9 and TSG101, consistent with canonical EV markers. Both renal and endothelial cells internalized PKH67-labeled AdEVs and exhibited increased IL-6 and IL-1B expression (p < 0.05). Renal cells demonstrated increased NGAL mRNA levels, whereas endothelial cells showed reduced eNOS mRNA expression following AdEV exposure (p < 0.05). CONCLUSION: AdEVs from SW872 upregulated cytokine (e.g., IL-6) and NGAL expression in renal cells, while reducing eNOS expression in endothelial cells. These findings suggest that AdEVs may influence early inflammatory and vascular responses inobesity.Ítem Progressive 11β-Hydroxysteroid Dehydrogenase Type 2 Insufficiency as Kidney Function Declines(Endocrine Society, 2024-09) Uslar, Thomas; Newman, Andrew J.; Tapia-Castillo, Alejandra; Carvajal, Cristian A.; Fardella, Carlos E.; Allende, Fidel; Solari, Sandra; Tsai, Laura C.; Milks, Julia; Cherney, Michael; Stouffer, David G.; Auchus, Richard; Brown, Jenifer M.; Baudrand, René; Vaidya, AnandBackground: It has been postulated that chronic kidney disease (CKD) is a state of relative 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) insufficiency, resulting in increased cortisol-mediated mineralocorticoid receptor (MR) activation. We hypothesized that relative 11βHSD2 insufficiency manifests across a wide spectrum of progressively declining kidney function, including within the normal range. Methods: Adult participants were recruited at 2 academic centers. A discovery cohort (n = 500) enrolled individuals with estimated glomerular filtration rate (eGFR) ranging from normal to CKD stage 5, in whom serum cortisol-to-cortisone (F/E) was measured as a biomarker of 11βHSD2 activity. A validation cohort (n = 101) enrolled only individuals with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2) in whom 11βHSD2 activity was assessed via serum F/E and 11-hydroxy-to-11-keto androgen (11OH/K) ratios following multiple maneuvers: oral sodium suppression test, dexamethasone suppression test (DST), and ACTH-stimulation test (ACTHstim). Results: In the discovery cohort, lower eGFR was associated with higher F/E (P-trend < .001). Similarly, in the validation cohort, with normal eGFR, an inverse association between eGFR and both F/E and 11OH/K ratios was observed (P-trend < .01), which persisted following DST (P-trend < .001) and ACTHstim (P-trend < .05). The fractional excretion of potassium, a marker of renal MR activity, was higher with higher F/E (P-trend < .01) and with lower eGFR (P-trend < .0001). Conclusion: A continuum of declining 11βHSD2 activity was observed with progressively lower eGFR in individuals spanning a wide spectrum of kidney function, including those with apparently normal kidney function. These findings implicate cortisol-mediated MR activation in the pathophysiology of hypertension and cardiovascular disease in CKD.Ítem Influence of estradiol deficiency on the mineralocorticoid receptor response in postmenopausal women: a cross-sectional study(Taylor & Francis Group, 2025-01) Martínez-García, Alejandra; Pérez, Jorge A.; Tapia-Castillo, Alejandra; Hernández, María P.; Solórzano, Marlin; Carrión, Pablo; Fardella, Carlos E.; Carvajal, Cristian A.Objective: Premenopausal women (PreM) have a cardioprotective advantage over postmenopausal women (PostM) due to estrogen. The interaction of estrogen with the mineralocorticoid receptor (MR) pathway remains unexplored. This study aimed to identify changes in aldosterone, renin and sexual steroid levels and MR surrogate biomarkers in PostM that may explain changes in blood pressure and renal damage. Methods: A cross-sectional study was carried out with 47 normotensive and hypertensive Chilean women distributed between PreM and PostM. Clinical, anthropometric and biochemical parameters, including aldosterone, plasma renin activity (PRA) and surrogate markers of MR activity, were assessed. Results: PostM had greater systolic blood pressure (SBP) (p < 0.001) than PreM. A negative correlation was observed between estradiol and fractional excretion of potassium (FEK) (ρ = –0.29; p = 0.023), adjusted for age and SBP. Compared with hypertensive PreM, hypertensive PostM (PostM-HT) showed reduced PRA (p = 0.045) and greater FEK (p = 0.04). Normotensive PostM (Post-NT) exhibited greater SBP (p = 0.03), neutrophil gelatinase-associated lipocalin (NGAL) levels (p = 0.04) and FEK (p = 0.03) than normotensive PreM. Conclusion: Our results suggest enhanced MR sensitivity not only in PostM-HT, as evidenced by lower PRA and elevated FEK, but also in PostM-NT, who exhibited greater FEK and NGAL levels, surrogate markers of MR activation. These results support a novel role of MR activation and cardiovascular risk in PostM women.Ítem Hipertensión arterial de origen endocrino en población pediátrica: Rol emergente del exceso aparente de mineralocorticoides no clásico(Sociedad Chilena de Endocrinología y Diabetes, 2026-01) Tapia-Castillo, Alejandra; Pérez, Jorge A.; Martínez-Aguayo, Alejandro; Carrión, Pablo; Pinilla, Renata; Hernández, María Paz; Martínez, Alejandra; Fardella, Carlos E.; Carvajal, Cristian A.La hipertensión arterial (HTA) pediátrica ha aumentado de manera sostenida en las últimas décadas, con una prevalencia estimada de 3–5% a nivel global y hasta 8% en Chile. Lejos de ser una condición benigna, la HTA en niños se asocia a daño temprano en órganos blanco, incluyendo hipertrofia ventricular izquierda, mayor grosor íntima-media carotídeo, rigidez arterial, microalbuminuria y alteraciones neurocognitivas. Mientras en escolares y adolescentes predomina la HTA primaria, en menores de seis años son más frecuentes las causas secundarias, entre ellas las endocrinas, que representan aproximadamente 5–10% de los casos y requieren una evaluación específica. Entre estas causas, el síndrome de Exceso Aparente de Mineralocorticoides (AME) destaca por una activación inapropiada del receptor mineralocorticoide (MR) mediada por cortisol, consecuencia de una actividad reducida o inhibida de la enzima 11β-hidroxiesteroide deshidrogenasa tipo 2 (11β-HSD2). El AME clásico es infrecuente y de presentación grave, asociado a variantes patogénicas en HSD11B2. En contraste, el AME no clásico (NC-AME) constituye una forma más leve y probablemente subdiagnosticada, caracterizada por renina baja, relación cortisol/cortisona elevada, niveles disminuidos de cortisona y aumento de la excreción urinaria de potasio, pudiendo contribuir a HTA en niños previamente considerados con HTA esencial. Los mecanismos propuestos para NCAME incluyen polimorfismos en HSD11B2, alteraciones epigenéticas y la presencia de inhibidores endógenos o exógenos de 11β-HSD2. En niños hipertensos, se han observado alteraciones del metabolismo del cortisol compatibles con una disfunción parcial de esta enzima. Aunque el uso de antagonistas del MR es eficaz en estos casos, el control óptimo de la presión arterial sigue siendo limitado. El NC-AME emerge, así como una causa relevante y subdiagnosticada de HTA pediátrica, subrayando la necesidad de mejorar su reconocimiento, caracterización y abordaje terapéutico.Ítem Primary Aldosteronism in a Hispanic Cohort: Responses to Mineralocorticoid Receptor Antagonism and Remission in a Case(Oxford University Press, 2025-02) Tapia-Castillo, Alejandra; Vecchiola, Andrea; Quiñones, Paola; Baudrand, René; Uslar, Thomas; Delgado, José; Carvajal, Cristian A.; Fardella, Carlos E.Background: Primary aldosteronism (PA) is the main cause of secondary arterial hypertension. In this study, we present the medical treatment of Hispanic patients with PA followed for up to 5 years, highlighting the complete cure with pharmacological treatment in one of our patients. Methods: We studied 32 PA patients, followed every 6 months after starting MRA. A clinical response was the normalization of blood pressure (BP) in the absence of other antihypertensive drugs. The biochemical response was considered with normalization of potassium and renin. Responses to treatment were compared using the defined daily dose (DDD). The effect of MRA was evaluated in vitro. The HAC15 cells were cultured and stimulated with aldosterone and spironolactone for 24-72 h, and the apoptotic cell death was measured. Results: At 12 months posttreatment with MRA, 68% of the patients had a total clinical response, and 67% had a total biochemical response. Response to MRA treatment reduced DDD by an average of 74%. Additionally, we observed one PA patient treated with spironolactone after 3 years, he presented a pharmacological cure with normalization of aldosterone and renin without treatment with spironolactone. The in vitro study shows that spironolactone increased early apoptosis by 60% and late apoptosis by 50%. Conclusions: These results suggest the importance of timely diagnosis of PA and specific treatment with MRA, especially in patients with a poor response to treatment. Moreover, remission of PA may occur in some patients after spironolactone treatment due to its suggestive role as an apoptotic agent.Ítem Driving hypertension: non-classic apparent mineralocorticoid excess(Springer Nature, 2025-11-12) Carvajal, Cristian A.; Tapia-Castillo, Alejandra; Uslar, Thomas; Vaidya, Anand; Pérez, Jorge A.; Baudrand, Rene; Fardella, Carlos E.Non-classic apparent mineralocorticoid excess is an underrecognized cause of low-renin hypertension, which is often misdiagnosed as essential hypertension. This condition challenges traditional classifications and highlights the need for mechanism-based diagnostics and medical care. Hypertension remains a leading contributor to global cardiovascular morbidity and mortality. It has a high prevalence, low rate of identifiable causes and is frequently resistant to conventional therapy. Hypertension is traditionally classified as ‘essential’ and multifactorial; however, up to one-third of patients have hypertension with a low-renin phenotype . This subtype has been largely attributed to primary aldosteronism, yet emerging data suggest a broader and more complex spectrum of mineralocorticoid receptor (MR) overactivation. Non-classic apparent mineralocorticoid excess (NC-AME) is one of several overlooked contributors to low-renin hypertension; NC-AME might account for a meaningful proportion of patients who have been misclassified as having essential hypertension.