RESUMEN

Aldosterone-producing adenoma is a subtype of primary aldosteronism. Recent advancements in multi-omics research have led to significant progress in understanding primary aldosteronism at the genetic level. Among the various genes associated with the development of aldosterone-producing adenomas, the KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) gene has received considerable attention due to its prevalence as the most common somatic mutation gene in primary aldosteronism. This paper aims to integrate the existing evidence on the involvement of KCNJ5 gene in the pathogenesis of aldosterone-producing adenomas, to enhance the understanding of the underlying mechanisms of aldosterone-producing adenomas from the perspective of genetics, and to provide novel insights for the clinical diagnosis and treatment of aldosterone-producing adenomas.

Asunto(s)

Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Aldosterona , Canales de Potasio Rectificados Internamente Asociados a la Proteína G , Hiperaldosteronismo , Humanos , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Aldosterona/metabolismo , Aldosterona/biosíntesis , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Adenoma/genética , Adenoma/metabolismo , Mutación

RESUMEN

Hypertension affects one-third of the adult population worldwide, with primary aldosteronism (PA) accounting for at least 5-10% of these cases. The aldosterone synthase enzyme (CYP11B2) plays a pivotal role in PA manifestation, as increased expression of CYP11B2 leads to excess aldosterone synthesis. Physiological expression of CYP11B2 in humans is normally limited to cells of the adrenal zona glomerulosa under tight homeostatic regulation. In PA, however, there are CYP11B2-positive lesions in the adrenal cortex that autonomously secrete aldosterone, highlighting the dysregulation of adrenal cortex zonation and function as a key aspect of PA pathogenesis. Thus, this review aims to summarize the development of the adrenal glands, the key regulators of adrenal cortex homeostasis, and the dysregulation of this homeostasis. It also discusses the development of CYP11B2 inhibitors for therapeutic use in patients with hypertension, as well as the current knowledge of the effects of CYP11B2 inhibition on adrenal cortex homeostasis and cell fate. Understanding the control of adrenal cell fate may offer valuable insights into both the pathogenesis of PA and the development of alternative treatment approaches for PA.

Asunto(s)

Glándulas Suprarrenales , Aldosterona , Citocromo P-450 CYP11B2 , Hiperaldosteronismo , Humanos , Aldosterona/metabolismo , Aldosterona/biosíntesis , Citocromo P-450 CYP11B2/metabolismo , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/patología , Glándulas Suprarrenales/metabolismo , Animales , Corteza Suprarrenal/metabolismo , Corteza Suprarrenal/citología , Hipertensión/metabolismo , Hipertensión/patología , Zona Glomerular/metabolismo , Diferenciación Celular , Homeostasis

RESUMEN

CONTEXT: The search for somatic mutations in adrenals resected from patients with primary aldosteronism (PA) is performed by Sanger sequencing, often implemented with immunohistochemistry (IHC)-guidance focused on aldosterone-producing (CYP11B2-positive) areas. OBJECTIVE: To investigate the impact of double IHC for CYP11B1 and CYP11B2 on Sanger and next-generation sequencing (NGS). METHODS: We investigated 127 consecutive adrenal aldosterone-producing adenomas from consenting surgically cured PA patients using double IHC for CYP11B1 and CYP11B2, by Sanger sequencing and NGS. RESULTS: Double IHC for CYP11B2 and CYP11B1 revealed 3 distinct patterns: CYP11B2-positive adenoma (pattern 1), mixed CYP11B1/CYP11B2-positive adenoma (pattern 2), and adrenals with multiple small CYP11B2-positive nodules (pattern 3). Sanger sequencing allowed detection of KCNJ5 mutations in 44% of the adrenals; NGS revealed such mutations in 10% of those negative at Sanger and additional mutations in 61% of the cases. Importantly the rate of KCNJ5 mutations differed across patterns: 17.8% in pattern 1, 71.4% in pattern 2, and 10.7% in pattern 3 (χ2 = 22.492, P < .001). CONCLUSION: NGS allowed detection of mutations in many adrenals that tested negative at Sanger sequencing. Moreover, the different distribution of KCNJ5 mutations across IHC patterns indicates that IHC-guided sequencing protocols selecting CYP11B2-positive areas could furnish results that might not be representative of the entire mutational status of the excised adrenal, which is important at a time when KCNJ5 mutations are suggested to drive management of patients with aldosterone-producing adenomas.

Asunto(s)

Citocromo P-450 CYP11B2 , Canales de Potasio Rectificados Internamente Asociados a la Proteína G , Hiperaldosteronismo , Inmunohistoquímica , Mutación , Esteroide 11-beta-Hidroxilasa , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Esteroide 11-beta-Hidroxilasa/genética , Esteroide 11-beta-Hidroxilasa/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Adulto , Secuenciación de Nucleótidos de Alto Rendimiento , Adenoma Corticosuprarrenal/genética , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Adenoma Corticosuprarrenal/diagnóstico , Anciano , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/patología

RESUMEN

Macrophages play crucial roles in organ-specific functions and homeostasis. In the adrenal gland, macrophages closely associate with sinusoidal capillaries in the aldosterone-producing zona glomerulosa. We demonstrate that macrophages preserve capillary specialization and modulate aldosterone secretion. Using macrophage-specific deletion of VEGF-A, single-cell transcriptomics, and functional phenotyping, we found that the loss of VEGF-A depletes PLVAP+ fenestrated endothelial cells in the zona glomerulosa, leading to increased basement membrane collagen IV deposition and subendothelial fibrosis. This results in increased aldosterone secretion, called "haptosecretagogue" signaling. Human aldosterone-producing adenomas also show capillary rarefaction and basement membrane thickening. Mice with myeloid cell-specific VEGF-A deletion exhibit elevated serum aldosterone, hypokalemia, and hypertension, mimicking primary aldosteronism. These findings underscore macrophage-to-endothelial cell signaling as essential for endothelial cell specialization, adrenal gland function, and blood pressure regulation, with broader implications for other endocrine organs.

Asunto(s)

Glándulas Suprarrenales , Aldosterona , Presión Sanguínea , Células Endoteliales , Macrófagos , Animales , Macrófagos/metabolismo , Aldosterona/metabolismo , Células Endoteliales/metabolismo , Ratones , Humanos , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Zona Glomerular/metabolismo , Zona Glomerular/patología , Masculino , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/patología , Hiperaldosteronismo/genética , Ratones Endogámicos C57BL

RESUMEN

Context: The prevalence of unilateral primary aldosteronism (UPA) with cortisol co-secretion varies geographically. Objective: To investigate the prevalence and clinical characteristics of UPA with cortisol co-secretion in a Chinese population. Design: Retrospective cohort study. Methods: We recruited 580 patients with UPA who underwent cosyntropin stimulation test (CST) after the 1-mg dexamethasone suppression test (DST) and retrospectively analyzed the clinical characteristics and postoperative outcomes of UPA with and without cortisol co-secretion. Results: UPA with cortisol co-secretion (1 mg DST>1.8 ug/dL) was identified in 65 of 580 (11.2%) patients. These patients were characterized by older age, longer duration of hypertension, higher concentration of plasma aldosterone and midnight cortisol, lower adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS), larger tumor diameter, and more history of diabetes mellitus. Cortisol and aldosterone levels were higher and DHEAS level was lower in UPA with cortisol co-secretion at 0-120 min after CST. Among 342 UPA patients with KCNJ5 gene sequencing and follow-up results, the complete clinical success rate was lower in UPA with cortisol co-secretion (33.3% vs. 56.4%, P<0.05); the complete biochemical success rate and KCNJ5 mutation did not differ between the two groups. Age, tumor size, and ACTH were independent predictors of UPA with cortisol co-secretion. Sex, BMI, duration of hypertension, KCNJ5 mutation, and cortisol co-secretion were independent predictors for complete clinical success in UPA after surgery. Conclusions: UPA with cortisol co-secretion is not uncommon in China, but the clinical features were distinctly different from those without co-secretion. Cortisol co-secretion is an independent risk factor for incomplete clinical success after surgery in UPA.

Asunto(s)

Hidrocortisona , Hiperaldosteronismo , Humanos , Hiperaldosteronismo/cirugía , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/sangre , Masculino , Femenino , Persona de Mediana Edad , Hidrocortisona/sangre , Estudios Retrospectivos , Adulto , Aldosterona/sangre , Adrenalectomía , China/epidemiología , Resultado del Tratamiento , Hormona Adrenocorticotrópica/sangre , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Estudios de Seguimiento , Pronóstico

RESUMEN

INTRODUCTION: The fluctuations of the intracellular Ca2+ concentration ([Ca2+]i) are key physiological signals for cell function under normal conditions and can undergo profound alterations in disease states, as high blood pressure due to endocrine disorders like primary aldosteronism (PA). However, when assessing such fluctuations several parameters in the Ca2+ signal dynamics need to be considered, which renders their assessment challenging. AIM: Aim to develop an observer-independent custom-made pipeline to analyze Ca2+ dynamics in terms of frequency and peak parameters, as amplitude, full width at half maximum (FWHM) and area under the curve (AUC). METHODS: We applied a custom-made methodology to aldosterone-producing adenoma (APA) and APA adjacent cells (AAC) and found this pipeline to be suitable for monitoring and processing a wide-range of [Ca2+]i events in these cell types delivering reproducible results. CONCLUSION: The designed pipeline can provide a useful tool for [Ca2+]i signal analysis that allows comparisons of Ca2+ dynamics not only in PA, but in other cell phenotypes that are relevant for the regulation of blood pressure.

Asunto(s)

Neoplasias de la Corteza Suprarrenal , Corteza Suprarrenal , Adenoma Corticosuprarrenal , Señalización del Calcio , Hiperaldosteronismo , Humanos , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Hiperaldosteronismo/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Adenoma Corticosuprarrenal/patología , Corteza Suprarrenal/metabolismo , Aldosterona/metabolismo , Calcio/metabolismo , Reproducibilidad de los Resultados , Células Cultivadas , Factores de Tiempo

RESUMEN

Few studies have investigated the hemodynamic mechanism whereby primary hyperaldosteronism causes hypertension. The traditional view holds that hyperaldosteronism initiates hypertension by amplifying salt-dependent increases in cardiac output (CO) by promoting increases in sodium retention and blood volume. Systemic vascular resistance (SVR) is said to increase only as a secondary consequence of the increased CO and blood pressure. Recently, we investigated the primary hemodynamic mechanism whereby hyperaldosteronism promotes salt sensitivity and initiation of salt-dependent hypertension. In unilaterally nephrectomized male Sprague-Dawley rats given infusions of aldosterone or vehicle, we found that aldosterone promoted salt sensitivity and initiation of salt-dependent hypertension by amplifying salt-induced increases in SVR while decreasing CO. In addition, we validated mathematical models of human integrative physiology, derived from Guyton's classic 1972 model - Quantitative Cardiovascular Physiology-2005 and HumMod-3.0.4. Neither model accurately predicted the usual changes in sodium balance, CO, and SVR that normally occur in response to clinically realistic increases in salt intake. These results demonstrate significant limitations with the hypotheses inherent in the Guyton models. Together these findings challenge the traditional view of the hemodynamic mechanisms that cause salt-sensitive hypertension in primary aldosteronism. Key words: Aldosterone, Blood pressure, Salt, Sodium, Rat.

Asunto(s)

Modelos Animales de Enfermedad , Hemodinámica , Hiperaldosteronismo , Hipertensión , Ratas Sprague-Dawley , Cloruro de Sodio Dietético , Animales , Hiperaldosteronismo/fisiopatología , Hiperaldosteronismo/metabolismo , Masculino , Hipertensión/fisiopatología , Hipertensión/etiología , Cloruro de Sodio Dietético/efectos adversos , Ratas , Hemodinámica/efectos de los fármacos , Aldosterona/sangre , Aldosterona/metabolismo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Modelos Cardiovasculares

RESUMEN

CONTEXT: Primary aldosteronism is a form of low-renin hypertension characterized by dysregulated aldosterone production. OBJECTIVE: To investigate the contributions of renin-independent aldosteronism and ACTH-mediated aldosteronism in individuals with a low-renin phenotype representing the entire continuum of blood pressure. DESIGN/PARTICIPANTS: Human physiology study of 348 participants with a low-renin phenotype with severe and/or resistant hypertension, hypertension with hypokalemia, elevated blood pressure and stage I/II hypertension, and normal blood pressure. SETTING: 4 international centers. INTERVENTIONS/MAIN OUTCOME MEASURES: The saline suppression test (SST) to quantify the magnitude of renin-independent aldosteronism; dexamethasone suppression and ACTH-stimulation tests to quantify the magnitude of ACTH-mediated aldosteronism; adrenal venous sampling to determine lateralization. RESULTS: There was a continuum of nonsuppressible and renin-independent aldosterone production following SST that paralleled the magnitude of the blood pressure continuum and transcended conventional diagnostic thresholds. In parallel, there was a full continuum of ACTH-mediated aldosteronism wherein post-SST aldosterone levels were strongly correlated with ACTH-stimulated aldosterone production (r = 0.75, P < .0001) and nonsuppressible aldosterone production postdexamethasone (r = 0.40, P < .0001). Beyond participants who met the criteria for primary aldosteronism (post-SST aldosterone of ≥10 ng/dL or ≥277 pmol/L), the continuum of nonsuppressible and renin-independent aldosterone production persisted below this diagnostic threshold, wherein 15% still had lateralizing aldosteronism amenable to surgical adrenalectomy and the remainder were treated with mineralocorticoid receptor antagonists. CONCLUSION: In the context of a low-renin phenotype, there is a continuum of primary aldosteronism and dysregulated aldosterone production that is prominently influenced by ACTH. A large proportion of individuals with low renin may benefit from aldosterone-directed therapy.

Asunto(s)

Hormona Adrenocorticotrópica , Aldosterona , Hiperaldosteronismo , Hipertensión , Renina , Humanos , Aldosterona/sangre , Aldosterona/metabolismo , Hiperaldosteronismo/metabolismo , Renina/sangre , Femenino , Masculino , Persona de Mediana Edad , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Hipertensión/etiología , Hipertensión/metabolismo , Adulto , Presión Sanguínea/fisiología , Anciano , Dexametasona , Glándulas Suprarrenales/metabolismo

RESUMEN

Objective: To investigate the diagnostic efficiency and prognostic value of 68Ga-Pentixafor PET/CT in comparison with adrenal vein sampling (AVS) for functional lateralization in primary aldosteronism (PA). Histology and long-term clinical follow-up normally serve as the gold standard for such diagnosis. Methods: We prospectively recruited 26 patients diagnosed with PA. All patients underwent 68Ga-Pentixafor PET/CT and AVS. Postsurgical biochemical and clinical outcomes of patients with unilateral primary aldosteronism (UPA), as diagnosed by PET/CT or AVS, were assessed by applying standardized Primary Aldosteronism Surgical Outcome (PASO) criteria. Immunohistochemistry (IHC) was performed to detect the expression of aldosterone synthase (CYP11B2) and CXCR4. Results: On total, 19 patients were diagnosed with UPA; of these, 13 patients were lateralized by both PET/CT and AVS, four patients were lateralized by PET-only, and two by AVS-only. Seven subjects with no lateralization on AVS and PET received medical therapy. All patients achieved complete biochemical success except one with nodular hyperplasia lateralized by AVS alone. The consistency between PET/CT and AVS outcomes was 77% (20/26). Moreover, CYP11B2-positive nodules were all CXCR4-positive and showed positive findings on PET. Patients who achieved complete biochemical and clinical success had a higher uptake on PET as well as stronger expression levels of CXCR4 and CYP11B2. Conclusion: Our analysis showed that 68Ga-Pentixafor PET/CT could enable non-invasive diagnosis in most patients with PA and identify additional cases of unilateral and surgically curable PA which could not be classified by AVS. 68Ga-Pentixafor PET/CT should be considered as a first-line test for the future classification of PA.

Asunto(s)

Complejos de Coordinación , Hiperaldosteronismo , Péptidos Cíclicos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Glándulas Suprarrenales/metabolismo , Radioisótopos de Galio/metabolismo , Citocromo P-450 CYP11B2/metabolismo , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirugía , Hiperaldosteronismo/metabolismo

RESUMEN

BACKGROUND: Primary aldosteronism (PA) is associated with increased metabolic risks. However, controversy exists as to which subtype of PA has a higher metabolic risk between bilateral and lateralized PA. This study aimed to assess the body composition of 2 PA subtypes, bilateral PA and lateralized PA, according to sex and autonomous cortisol secretion (ACS) and their contribution to comorbidities. DESIGN AND METHODS: A total of 400 patients with PA (females, n = 210) and 1:10 age- and sex-matched healthy controls (n = 4000) were enrolled. The skeletal muscle area (SMA), subcutaneous fat area, and visceral fat area (VFA) at the third lumbar spine were calculated using abdominal computed tomography-based body composition analysis. RESULTS: Patients with bilateral PA had higher body mass index (BMI) in both sexes (all P < .05). Hemoglobin A1c level and the prevalence of diabetes were higher in female patients with bilateral PA than in those with lateralized PA (all P < .05). The VFA/BMI ratio was significantly higher in bilateral PA patients than in lateralized PA patients (5.77 ± 2.69 vs 4.56 ± 2.35 in men; 4.03 ± 2.58 vs 2.53 ± 2.05 in women, all P < .001). PA patients with ACS showed decreased SMA compared to those without ACS. Compared with healthy controls, all patients with bilateral PA and female patients with lateralized PA showed significantly higher VFA and VFA/BMI. CONCLUSIONS: Patients with bilateral PA were more obese and had higher VFA levels than those with lateralized PA. Despite a milder form of PA, this metabolically unfavorable visceral fat distribution may lead to a higher metabolic risk in patients with bilateral PA.

Asunto(s)

Diabetes Mellitus , Hiperaldosteronismo , Masculino , Humanos , Femenino , Composición Corporal , Obesidad/complicaciones , Obesidad/epidemiología , Obesidad/metabolismo , Diabetes Mellitus/epidemiología , Índice de Masa Corporal , Grasa Intraabdominal/diagnóstico por imagen , Grasa Intraabdominal/metabolismo , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/epidemiología , Hiperaldosteronismo/metabolismo

RESUMEN

11Beta-hydroxysteroid dehydrogenase 1 (11ß-HSD1) is a key enzyme involved in metabolic syndrome. Transcript-specific epigenetic regulation of the gene encoding 11ß-HSD1 (HSD11B1) has been reported. We examined the mRNA level and methylation status of the HSD11B1 promoter region in the adipose tissue of patients with primary aldosteronism (PA). We compared 10 tissue specimens from patients with PA caused by aldosterone-producing adenoma (APA) with 8 adipose tissue specimens from patients with subclinical Cushing's syndrome (SCS) caused by cortisol-producing adenomas, 4 tissue specimens from patients with Cushing's adenoma (Cu), or 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). PA, SCS, and Cu were diagnosed according to the guideline of the Japan Endocrine Society. The mRNA level of HSD11B1 was quantified using real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific to the human HSD11B1 promoter region. The glycohemoglobin level was significantly higher in patients with APA, SCS, or Cu than in those with NFA (p < 0.05). Blood pressure was significantly higher in patients with APA than in those with SCS, Cu, or NFA (p < 0.01). The HSD11B1 mRNA level was significantly increased in the adipose tissues of APA or SCS patients compared with Cu or NFA patients (p < 0.05). The methylation ratio was significantly lower in SCS patients than in APA, Cu, or NFA patients (p < 0.05). HSD11B1 expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological role of epigenetic regulation of HSD11B1 expression in adipose tissue requires further study.

Asunto(s)

Adenoma , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Humanos , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Epigénesis Genética , Tejido Adiposo/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Adenoma/metabolismo , ARN Mensajero/metabolismo

RESUMEN

Primary aldosteronism (PA) causes 5-10% of hypertension cases, but only a minority of patients are currently diagnosed and treated because of a complex, stepwise, and partly invasive workup. We tested the performance of urine steroid metabolomics, the computational analysis of 24-hour urine steroid metabolome data by machine learning, for the identification and subtyping of PA. Mass spectrometry-based multi-steroid profiling was used to quantify the excretion of 34 steroid metabolites in 24-hour urine samples from 158 adults with PA (88 with unilateral PA [UPA] due to aldosterone-producing adenomas [APAs]; 70 with bilateral PA [BPA]) and 65 sex- and age-matched healthy controls. All APAs were resected and underwent targeted gene sequencing to detect somatic mutations associated with UPA. Patients with PA had increased urinary metabolite excretion of mineralocorticoids, glucocorticoids, and glucocorticoid precursors. Urine steroid metabolomics identified patients with PA with high accuracy, both when applied to all 34 or only the three most discriminative steroid metabolites (average areas under the receiver-operating characteristics curve [AUCs-ROC] 0.95-0.97). Whilst machine learning was suboptimal in differentiating UPA from BPA (average AUCs-ROC 0.65-0.73), it readily identified APA cases harbouring somatic KCNJ5 mutations (average AUCs-ROC 0.79-85). These patients showed a distinctly increased urine excretion of the hybrid steroid 18-hydroxycortisol and its metabolite 18-oxo-tetrahydrocortisol, the latter identified by machine learning as by far the most discriminative steroid. In conclusion, urine steroid metabolomics is a non-invasive candidate test for the accurate identification of PA cases and KCNJ5-mutated APAs.

Asunto(s)

Adenoma , Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Adulto , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Adenoma Corticosuprarrenal/genética , Adenoma/diagnóstico , Esteroides , Espectrometría de Masas , Aldosterona/metabolismo , Mutación , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Neoplasias de la Corteza Suprarrenal/genética

RESUMEN

The human adrenal cortex secretes aldosterone and cortisol as major corticosteroids. For their production, CYP11B2 and CYP11B1 catalyze the last steps in the syntheses of aldosterone and cortisol, respectively. In our previous study, CYP11B2 was the first successfully purified from rat adrenals and human clinical samples and then was proved to be aldosterone synthase. We demonstrated the immunohistochemistry for CYP11B2 of both rats and humans and applied it clinically to visualize the functional histology of aldosterone-producing adenoma (APA) causing primary aldosteronism (PA). We discovered aldosterone-producing cell clusters (APCCs) and possible APCC-to-APA transitional lesions (pAATLs) and further visualized aldosterone-producing lesions for rare forms of PA including familial hyperaldosteronism type 3 and novel non-familial juvenile PA. Here we review the history of our research on aldosterone-producing lesions.

Asunto(s)

Neoplasias de la Corteza Suprarrenal , Hiperaldosteronismo , Humanos , Animales , Ratas , Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Hidrocortisona , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Mutación

RESUMEN

Adrenal vein sampling (AVS) is recommended for subtyping primary aldosteronism (PA) to identify lateralized or bilateral sources of aldosterone excess, allowing for better decision-making in regard to medical or surgical management on a case-by-case basis. To date, no consensus exists on protocols to be used during AVS, especially concerning sampling techniques, the timing of sampling, and whether or not to use adrenocorticotropic hormone (ACTH) stimulation. Interpretation criteria for selectivity, lateralization, and contralateral suppression vary from one expert center to another, with some favoring strict cut-offs to others being more permissive. Clinical and biochemical post-operative outcomes can also be influenced by AVS criteria utilized to indicate surgical therapy.In this review, we reanalyze studies on AVS highlighting the recent pathological findings of frequent micronodular hyperplasia adjacent to a dominant aldosteronoma (APA) overlapping with bilateral idiopathic hyperaldosteronism (IHA) etiologies, as opposed to the less frequent unilateral single aldosteronoma. The variable expression of melanocortin type 2 receptors in the nodules and hyperplasia may explain the frequent discordance in lateralization ratios between unstimulated and ACTH- stimulated samples. We conclude that aldosterone values collected during simultaneous bilateral sampling, both at baseline and post-ACTH stimulation, are required to adequately evaluate selectivity, lateralization, and contralateral suppression during AVS, to better identify all patients with PA that can benefit from a surgical indication. Recommended cut-offs for each ratio are also presented.

Asunto(s)

Glándulas Suprarrenales , Hiperaldosteronismo , Humanos , Glándulas Suprarrenales/cirugía , Glándulas Suprarrenales/irrigación sanguínea , Glándulas Suprarrenales/metabolismo , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/cirugía , Hiperaldosteronismo/metabolismo , Aldosterona/metabolismo , Hiperplasia/patología , Hormona Adrenocorticotrópica/metabolismo , Estudios Retrospectivos

RESUMEN

PURPOSE OF REVIEW: An increasing amount of evidence points out to a role for the thiazide-sensitive Na+:Cl- cotransporter, NCC, in the blood pressure alterations observed in conditions of pathologically high or pathologically low aldosterone. Here, we briefly review this evidence that is changing our perception of the pathophysiology of primary aldosteronism. RECENT FINDINGS: Although initially NCC was thought to be a direct target of aldosterone, more recent evidence suggests that NCC is only indirectly regulated by aldosterone, at least in a chronic setting. Aldosterone-induced changes in plasma K+ concentration that are prompted by the modulation of K+ secretion in principal cells of the connecting tubule and collecting duct are actually responsible for the modulation of NCC in conditions of altered aldosterone levels. A mounting amount of evidence suggests that this indirect effect of aldosterone on NCC may be key to produce the blood pressure alterations observed in aldosterone excess or aldosterone deficit. Finally, recent insights into the molecular pathways involved in NCC modulation by K+ are briefly reviewed. SUMMARY: The evidence reviewed here suggests that correction of K+ alterations in patients with hyper or hypoaldosteronism may substantially affect blood pressure levels. Mechanistically, this may be related to the K+-mediated modulation of NCC.

Asunto(s)

Hiperaldosteronismo , Hipertensión , Humanos , Aldosterona/metabolismo , Fosforilación , Hipertensión/etiología , Hipertensión/metabolismo , Presión Sanguínea , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Túbulos Renales Distales/metabolismo

RESUMEN

BACKGROUND: Primary aldosteronism is frequently caused by an adrenocortical aldosterone-producing adenoma (APA) carrying a somatic mutation that drives aldosterone overproduction. APAs with a mutation in KCNJ5 (APA-KCNJ5MUT) are characterized by heterogeneous CYP11B2 (aldosterone synthase) expression, a particular cellular composition and larger tumor diameter than those with wild-type KCNJ5 (APA-KCNJ5WT). We exploited these differences to decipher the roles of transcriptome and metabolome reprogramming in tumor pathogenesis. METHODS: Consecutive adrenal cryosections (7 APAs and 7 paired adjacent adrenal cortex) were analyzed by spatial transcriptomics (10x Genomics platform) and metabolomics (in situ matrix-assisted laser desorption/ionization mass spectrometry imaging) co-integrated with CYP11B2 immunohistochemistry. RESULTS: We identified intratumoral transcriptional heterogeneity that delineated functionally distinct biological pathways. Common transcriptomic signatures were established across all APA specimens which encompassed 2 distinct transcriptional profiles in CYP11B2-immunopositive regions (CYP11B2-type 1 or 2). The CYP11B2-type 1 signature was characterized by zona glomerulosa gene markers and was detected in both APA-KCNJ5MUT and APA-KCNJ5WT. The CYP11B2-type 2 signature displayed markers of the zona fasciculata or reticularis and predominated in APA-KCNJ5MUT. Metabolites that promote oxidative stress and cell death accumulated in APA-KCNJ5WT. In contrast, antioxidant metabolites were abundant in APA-KCNJ5MUT. Finally, APA-like cell subpopulations-negative for CYP11B2 gene expression-were identified in adrenocortical tissue adjacent to APAs suggesting the existence of tumor precursor states. CONCLUSIONS: Our findings provide insight into intra- and intertumoral transcriptional heterogeneity and support a role for prooxidant versus antioxidant systems in APA pathogenesis highlighting genotype-dependent capacities for tumor expansion.

Asunto(s)

Adenoma , Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Humanos , Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Antioxidantes , Multiómica , Hiperaldosteronismo/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Genotipo , Mutación , Adenoma/metabolismo , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/complicaciones

RESUMEN

Aldosterone, a vital hormone of the human body, has various pathophysiological roles. The excess of aldosterone, also known as primary aldosteronism, is the most common secondary cause of hypertension. Primary aldosteronism is associated with an increased risk of cardiovascular disease and kidney dysfunction compared to essential hypertension. Excess aldosterone can lead to harmful metabolic and other pathophysiological alterations, as well as cause inflammatory, oxidative, and fibrotic effects in the heart, kidney, and blood vessels. These alterations can result in coronary artery disease, including ischemia and myocardial infarction, left ventricular hypertrophy, heart failure, arterial fibrillation, intracarotid intima thickening, cerebrovascular disease, and chronic kidney disease. Thus, aldosterone affects several tissues, especially in the cardiovascular system, and the metabolic and pathophysiological alterations are related to severe diseases. Therefore, understanding the effects of aldosterone on the body is important for health maintenance in hypertensive patients. In this review, we focus on currently available evidence regarding the role of aldosterone in alterations of the cardiovascular and renal systems. We also describe the risk of cardiovascular events and renal dysfunction in hyperaldosteronism.

Asunto(s)

Enfermedades Cardiovasculares , Hiperaldosteronismo , Hipertensión , Humanos , Aldosterona/metabolismo , Enfermedades Cardiovasculares/metabolismo , Hipertensión/metabolismo , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/metabolismo , Hipertensión Esencial/complicaciones

RESUMEN

The initial isolation of adrenal steroids from large quantities of animal adrenals resulted in an amorphous fraction resistant to crystallization and identification and had potent effects on electrolyte transport. Aldosterone was eventually isolated and identified in the fraction and was soon shown to cause hypertension when in excess. The autonomous and excessive production of aldosterone, primary aldosteronism, is the most common cause of secondary hypertension. Aldosterone is metabolized in the liver and kidney, and its metabolites are conjugated with glucuronic acid for excretion. The most common liver metabolite is 3α,5ß-tetrahydroaldosterone-3-glucuronide, while that of the kidney is aldosterone-18-oxo-glucuronide. In terms of their value, especially the aldosterone-18-oxo-glucuronide, is commonly used for the diagnosis of primary aldosteronism because they provide an integrated value of the total daily production of aldosterone. Conversion of aldosterone to 18-oxo-glucuronide is impeded by drugs, like some common non-steroidal anti-inflammatory drugs that compete for UDP-glucuronosyltransferase-2B7, the most important glucuronosyltransferase for aldosterone metabolism. Tetrahydroaldosterone is the most abundant metabolite and the most reliable for the diagnosis of primary aldosteronism, but it is not commonly measured.

Asunto(s)

Hiperaldosteronismo , Hipertensión , Animales , Aldosterona/metabolismo , Glucurónidos , Hipertensión/etiología , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/metabolismo , Glucuronosiltransferasa

RESUMEN

BACKGROUND: Aldosterone-producing adenoma (APA) is a benign adrenal tumor with autonomous aldosterone production which causes hypertension and excess cardiovascular risk. Protein phosphorylation regulates aldosterone secretion from adrenal cortical cells, but how signaling networks are remodeled in APA remains unknown. METHODS: We performed an integrated proteomic and phosphoproteomic profiling of 15 APA and 10 matched nonfunctioning adrenocortical tumors (NFAT) based on the 4-dimensional label-free technique. We further validated our main findings in enlarged APA samples, mice, and adrenocortical cell line. RESULTS: The proteomic and phosphoproteomic profiling of APA and NFAT quantified 5989 proteins and 9011 phosphopeptides. We highlighted differentially expressed and phosphorylated proteins which modulated aldosterone synthesis and secretion from APA. As intracellular calcium is the central signal for aldosterone synthesis, our integrated calcium signaling network implicated wolframin in the control of calcium influx and CYP11B2 (aldosterone synthase) activation in APA (ratio of wolframin expression in APA to NFAT: 6.411, P<0.001). Among 97 APA cases for validation, a higher expression level of wolframin was associated with a higher plasma aldosterone concentration postcaptopril challenge test and a higher systolic blood pressure. In vitro, the secretion of aldosterone was enhanced by wolframin overexpression, while aldosterone secretion in response to potassium or angiotensin II was inhibited by the knockdown of wolframin. Further in vivo and in vitro data demonstrated the wolframin-calcium axis as an important regulator of CYP11B2 expression and aldosterone production. CONCLUSIONS: Wolframin is a regulatory protein in aldosterone hypersecretion. Remodeled calcium transportation and mitochondrial function are involved in wolframin-related aldosterone secretion.

Asunto(s)

Neoplasias de la Corteza Suprarrenal , Adenoma Corticosuprarrenal , Hiperaldosteronismo , Animales , Ratones , Neoplasias de la Corteza Suprarrenal/metabolismo , Adenoma Corticosuprarrenal/metabolismo , Aldosterona/metabolismo , Calcio/metabolismo , Señalización del Calcio , Citocromo P-450 CYP11B2/metabolismo , Hiperaldosteronismo/metabolismo , Proteómica

Asunto(s)

Aldosterona , Hipertensión , Humanos , Aldosterona/metabolismo , Hiperaldosteronismo/complicaciones , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/metabolismo , Hipertensión/tratamiento farmacológico , Hipertensión/metabolismo , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Monitoreo Fisiológico