UNASSIGNED: Foetal growth restriction (FGR) occurs when a foetus fails to reach its growth potential. This observational study assessed the expression and significance of cell migration-including protein (CEMIP) and aldosterone synthase (CYP11B2) in the serum of pregnant women with FGR.
UNASSIGNED: 40 singleton FGR-suffered pregnant women, as well as 40 normal singleton pregnant women, were enrolled. The expression of CEMIP and CYP11B2 in serum was detected in early pregnancy. The correlations between parameters were evaluated. The predictive variables for FGR were determined. The diagnostic value of CEMIP and CYP11B2 for FGR was analysed.
UNASSIGNED: CEMIP and CYP11B2 mRNA expression in the serum of pregnant women with FGR decreased (both P < 0.001). CEMIP (95%CI: 0.802-0.921, P < 0.001) and CYP11B2 (95%CI: 0.795-0.907, P < 0.001) mRNA expression in serum and soluble fms like tyrosine kinase-1 (sFLT1)/placental growth factor (PlGF) ratio (95%CI: 0.866-0.974, P < 0.001) were independent predictors of FGR, and CEMIP (r = -0.578, P = 0.001) and CYP11B2 (r = -0.602, P < 0.001) mRNA expression in serum were negatively correlated with sFLT1/PlGF ratio. CEMIP (AUC = 0.741) and CYP11B2 (AUC = 0.764) mRNA expression in serum had good diagnostic value for FGR.
UNASSIGNED: The expression of CEMIP and CYP11B2 is reduced in the serum of pregnant women with FGR and may become new diagnostic markers for FGR.
Foetal growth restriction is the inability of the foetus to reach its growth potential in the uterus due to various factors. This study aimed to investigate the expression and significance of cell migration-including protein and aldosterone synthase in serum of pregnant women with foetal growth restriction. In our study, we found that the expression of cell migration-including protein and aldosterone synthase in serum of pregnant women with foetal growth restriction were decreased. Cell migration-including protein and aldosterone synthase expression was negatively correlated with soluble fms like tyrosine kinase-1/placental growth factor ratio. In addition, the study also found that cell migration-including protein and aldosterone synthase expression in serum had good diagnostic value for foetal growth restriction.

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.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.

Activation of the renin-angiotensin-aldosterone system (RAAS) plays an important pathophysiological role in hypertension. Increased mRNA levels of the angiotensinogen angiotensin-converting enzyme, angiotensin type 1 receptor gene, Agtr1a, and the aldosterone synthase gene, CYP11B2, have been reported in the heart, blood vessels, and kidneys in salt-sensitive hypertension. However, the mechanism of gene regulation in each component of the RAAS in cardiovascular and renal tissues is unclear. Epigenetic mechanisms, which are important for regulating gene expression, include DNA methylation, histone post-translational modifications, and microRNA (miRNA) regulation. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in visceral adipose tissue and the heart of salt-sensitive hypertensive rats. Several miRNAs influence AGT expression and are associated with cardiovascular diseases. Expression of both ACE and ACE2 genes is regulated by DNA methylation, histone modifications, and miRNAs. Expression of both angiotensinogen and CYP11B2 is reversibly regulated by epigenetic modifications and is related to salt-sensitive hypertension. The mineralocorticoid receptor (MR) exists in cardiovascular and renal tissues, in which many miRNAs influence expression and contribute to the pathogenesis of hypertension. Expression of the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene is also regulated by methylation and miRNAs. Epigenetic regulation of renal and vascular HSD11B2 is an important pathogenetic mechanism for salt-sensitive hypertension.

The distribution of CYP11B2-positive or aldosterone producing adrenocortical cells in human fetuses and children and their age-dependent changes has not been studied. We aimed to explore the changes of aldosterone biosynthesis and age-related histological alterations of the zona glomerulosa in human adrenal gland during fetal and pediatric periods. We first reviewed 125 fetal and pediatric autopsy cases and retrieved 78 adrenals from 70 cases. CYP11B2 immunohistochemistry and quantitative image analysis of its results were performed in all adrenal glands. The ratio of the definitive zone (DZ) or zona glomerulosa (ZG) / the whole adrenocortical areas started to increase in the 2nd trimester, subsequently decreased in the 3rd, increased after birth, peaked in infancy, and then gradually decreased. The ratio of CYP11B2-positive / whole adrenocortical areas remained low during the fetal period but increased after birth, peaked at infancy, and then decreased. The ratio of CYP11B2-positive / DZ or ZG areas and CYP11B2-positive areas / depth of DZ or ZG demonstrated a distinctive bimodal pattern, with one peak in the fetal period and another in the neonatal period to infancy. This is the first study to perform quantitative analysis of the distribution of CYP11B2-positive cells, the histological DZ or ZG, and the development of aldosterone biosynthesis in human adrenal glands during fetal and pediatric periods.

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1β, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management.

4-[(5-[2-Methyl-5-(methylsulfonyl)pentan-2-yl]sulfonylpyrimidin-4-yl)amino]benzonitrile 2 was identified as a novel potent aldosterone synthase inhibitor. Compound 2 was found to inhibit human CYP11B2 in the nanomolar range, and showed an aldosterone-lowering effect in a furosemide-treated cynomolgus monkey model. Although human CYP11B2 has the high homology sequence with human CYP11B1, compound 2 showed more than 80 times higher selectivity over human CYP11B1 in vitro.

Aldosterone synthase (CYP11B2) is the rate-limiting enzyme in aldosterone production. In recent years, CYP11B2 has become an appealing target for treating conditions associated with excess aldosterone, such as hypertension, heart failure, and cardiometabolic diseases. Several small-molecule inhibitors of CYP11B2 have demonstrated efficacy in both preclinical studies and clinical trials. Among them, the tetrahydroisoquinoline derivative Baxdrostat has entered clinical trial phases and demonstrated efficacy in treating patients with hypertension. However, the high homology (>93 %) between CYP11B2 and steroid-11β-hydroxylase (CYP11B1), which catalyzes cortisol production, implies that insufficient drug specificity can lead to severe side effects. Developing selective inhibitors for CYP11B2 remains a considerable challenge that requires ongoing attention. This review summarizes recent research progress on small-molecule inhibitors targeting CYP11B2, focusing on structure-activity relationships (SAR) and structural optimization. It discusses strategies for enhancing the specificity and inhibitory activity of inhibitors, while also exploring potential applications and future prospects for CYP11B2 inhibitors, providing a theoretical foundation for developing the new generation of CYP11B2-targeted medications.

We have previously described local aldosterone synthesis in mouse colon. In the renin-angiotensin-aldosterone system (RAAS), angiotensin II (Ang II) peptide is the physiological factor which stimulates aldosterone synthesis in the adrenal glands. We have recently demonstrated that Ang II stimulates aldosterone synthesis also in mouse colon. Here, we conducted a 75-min ex vivo incubation of murine colonic tissue and evaluated the effects of three other Ang peptides, Ang I (1 μM), Ang III (0.1 μM) and Ang (1-7) (0.1 μM) on aldosterone synthesis. As a possible mechanism, their effects on tissue levels of the rate-limiting enzyme, aldosterone synthase (CYP11B2) were measured by ELISA and Western blot. Ang III significantly elevated the amount of tissue CYP11B2 protein in colon. The values of released aldosterone in colon tissue incubation were increased over the control in the presence of Ang I, II or III, however, being statistically non-significant. In Western blot analysis, the values of tissue CYP11B2 protein content were elevated by Ang I and II. Ang (1-7) alone in colon did not influence CYP11B2 protein levels in the incubation experiment but showed higher aldosterone release without statistical significance. Ang (1-7) showed an antagonistic effect towards Ang II in release of aldosterone in adrenal gland. An overall estimation of a single peptide (three measured variables), the results were always in an increasing direction. The responses of aldosterone synthesis to high levels of glucose (44 mM) and potassium (18.8 mM) as physiological stimulators in vivo were investigated in the colon incubation. Glucose, equal to four times the concentration of the control buffer in the incubation, showed higher values of aldosterone release in colon than control without statistical significance similarly to the effect seen in adrenal glands. Increasing the concentration of potassium in the incubation buffer exerted no effect on colonic aldosterone production. Intriguingly, no correlation was found between aldosterone release and the tissue CYP11B2 protein content in colon. In summary, the response of colonic aldosterone synthesis to different Ang peptides resembles, but is not identical to, the situation in the adrenal glands.

Despite being the world\'s top risk factor for death and disability, hypertension awareness and control within the chronic kidney disease (CKD) population have decreased. This is particularly important considering the heightened severity and management challenges of hypertension in CKD patients, whose outcomes are often worse compared with persons with normal kidney function. Therefore, finding novel therapeutics to improve blood pressure control within this vulnerable group is paramount. Although medications that target the renin-angiotensin-aldosterone system remain a mainstay for blood pressure control in most stages of CKD, we discuss novel approaches that may expand their use in advanced CKD. We also review newer tools for blood pressure management that have emerged in recent years, including aldosterone synthase inhibitors, endothelin receptor antagonists, and renal denervation. Overall, the future of hypertension management in CKD appears brighter, with a growing arsenal of tools and a deeper understanding of this complex disease.