Search

Objective: Primary aldosteronism has two main clinically and biologically distinct subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). We aimed to evaluate the changes of each subtype's clinical characteristics over a 13-year period., Methods: This retrospective study involved time-trend analyses to identify changes in the clinical features of APA and BAH at diagnosis (2006-2018). A nationwide database from 41 Japanese referral centers was searched, which identified 2804 primary aldosteronism patients with complete baseline information and adrenal venous sampling (AVS) data., Results: The proportion of patients with APA decreased from 51% in 2006-2009 to 22% in 2016-2018. Among the 1634 patients with BAH, trend analyses revealed decreases in hypertension duration (median 7--3 years; P < 0.01) and hypokalemia prevalence (18--11%; P < 0.01). However, among the 952 patients with APA, there were no significant changes in hypertension duration (median 8 years) and hypokalemia prevalence (overall 70%). Furthermore, the APA group had a trend towards increased use of multiple hypertensive drugs at diagnosis (30--43%; P < 0.01). When subtypes were reclassified according to the precosyntropin stimulation AVS data, APA patients tended to be diagnosed earlier and at milder forms, consistent with the trend in overall primary aldosteronism patients., Conclusion: During 2006-2018, we identified marked subtype-specific trends in the clinical findings at the diagnosis of primary aldosteronism. Our results suggested that the emphasis on the implementing cosyntropin stimulation during AVS might lead to under-identification of APA, especially in patients with mild or early cases., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Aldosterone synthase gene, CYP11B2 is regulated by potassium and angiotensin II (Ang II). We have reported that Ang II could change the DNA methylation status around transcription factor-binding sites and a transcription start site (TSS) and activate expression of CYP11B2. Similar to Ang II, small increases in extracellular potassium levels also increase CYP11B2 mRNA levels., Methods and Results: Adrenocortical H295R cells were treated with different doses of potassium. Methylation analysis of CYP11B2 promoter region was done by bisulfite sequencing. CYP11B2 mRNA and protein levels, chromatin accessibility, methylation and demethylation activity were estimated. The transcriptional ability of CYP11B2 promoter with or without methylation was assessed. Potassium stimulation caused DNA demethylation around cyclic AMP responsive element binding protein 1 (CREB1) and nuclear receptor subfamily 4 group A (NR4A) family-binding sites and a TSS; demethylation was accompanied by recruitment of CREB1 and NR4A1 and increased chromatin accessibility of the CYP11B2 promoter. DNA methylation activity decreased in the nucleus. DNA demethylation at CpG1 (Ad1), CpG2 (Ad5) and CpG3 were detected within 2 to 4 days after potassium (16 mmol/l) stimulation. The changes reached a maximum level by day 7. DNA at CpG2 (Ad5) and CpG3 was re-methylated to levels that were similar to those of nontreated cells at day 9. Potassium treatment significantly reduced DNA methylation activity at days 7 and 9. DNA demethylation activity was not changed by potassium., Conclusion: : Potassium induced reversibly DNA demethylation, which switches the phenotype of CYP11B2 expression from an inactive to an active state., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Adrenal venous sampling (AVS) is essential for identifying a surgically curable form of primary aldosteronism. Adrenocorticotropic hormone (ACTH) infusion or bolus has been reported to improve the success rate of AVS, although the effects on lateralization and its outcomes in unilateral primary aldosteronism are unclear., Methods: The success rate and lateralization indices were examined in a cohort of 2197 Japanese patients with primary aldosteronism from 28 centres who underwent AVS. Outcomes were analysed in 267 patients with aldosterone-producing adenomas (APAs)., Results: ACTH loading during AVS improved the success rate from 67 to 89%, while lateralization indices decreased from 62 to 28%. Bolus, bolus along with continuous infusion or continuous infusion of ACTH did not affect both indices. The absence of clinical success (i.e. unchanged or increased blood pressure) was 33% and absence of biochemical success (persistent hypokalaemia or persistently raised aldosterone-to-renin ratio, or both) was 15%. The clinical and biochemical success rates did not differ between the three groups [lateralization index >2 in basal condition (LIb) and lateralization index >4 after ACTH loading (lateralization indices), and LIb >2 + lateralization indices<4, LIb<2+lateralization indices>4]. The three groups (LIb>4+lateralization indices>4, LIb>4+lateralization indices<4 and LIb<4+lateralization indices>4) did not show any significant differences of clinical and biochemical outcome., Conclusion: ACTH loading during AVS improved the success rate but decreased laterality. ACTH did not affect the clinical and biochemical outcomes in APA patients. These data showed that the use of ACTH during AVS was helpful for improving the success rate, but did not contribute to better outcomes.

Background: The (pro)renin receptor exists in the kidney, blood vessels and the heart. (Pro)renin binds to the receptor and induces tissue injuries directly, completely independent of angiotensin II (Ang II). The renal renin-angiotensin-aldosterone system is activated in salt-sensitive hypertensive rats with in-vitro studies showing aldosterone increases angiotensin-converting enzyme (ACE) activity, renin production and angiotensin II type 1 receptor (AT1R) activity. However, the effect of blockade of mineralocorticoid receptor on the renal (pro)renin receptor, angiotensinogen, ACE and AT1R in Dahl salt-sensitive rats is unknown., Methods: The following parameters were measured in Dahl salt-sensitive rats and in Dahl salt-resistant rats fed high-salt or low-salt diets and treated for 8 weeks with or without eplerenone (100 mg/kg per day, orally): blood pressure, plasma renin activity, plasma aldosterone concentration, kidney weight and Ang II contents, urinary protein excretion, glomerular injury (assessed by semiquantitative morphometric analysis) and levels of expression in the kidney of (pro)renin receptor protein and messenger RNA (mRNA) for angiotensinogen, ACE and AT1R., Results: Dahl salt-sensitive rats fed a high-salt diet had increased kidney/body weight (175%) and urinary protein excretion (886%) and decreased plasma renin activity and plasma aldosterone concentration. The rats developed progressive sclerotic and proliferative glomerular changes, concomitant with increased expression of renal (pro)renin receptor protein and mRNA levels of angiotensinogen, ACE and AT1R and kidney Ang II content. Treatment with eplerenone in Dahl salt-sensitive rats was associated with significant improvements in kidney to body weight ratio, urinary protein excretion and renal injury scores and decreased renal (pro)renin receptor protein expression and angiotensinogen and AT1R mRNA levels and kidney Ang II content., Conclusion: A high salt diet increased the renal renin-angiotensin system, whereas blockade of mineralocorticoid receptors attenuated renal injuries by decreasing the activity of tissue renin-angiotensin system in Dahl salt-sensitive rats.