Downregulation of exosomal miR-192-5p and miR-204-5p in subjects with nonclassic apparent mineralocorticoid excess

Abstract

BackgroundThe “nonclassic” apparent mineralocorticoid excess (NC-AME) has been identified in approximately 7% of general population. This phenotype is characterized by low plasma renin activity (PRA), high serum cortisol (F) to cortisone (E) ratio, low cortisone, high Fractional Excretion of potassium (FEK) and normal-elevated systolic blood pressure (SBP). An early detection and/or identification of novel biomarkers of this phenotype could avoid the progression or future complications leading to arterial hypertension. Isolation of extracellular vesicles, such as exosomes, in specific biofluids support the identification of tissue-specific RNA and miRNA, which may be useful as novel biomarkers. Our aim was to identify miRNAs within urinary exosomes associated to the NC-AME phenotype.MethodsWe perform a cross-sectional study in a primary care cohort of 127 Chilean subjects. We measured BP, serum cortisol, cortisone, aldosterone, PRA. According to the previous reported, a subgroup of subjects was classified as NC-AME (n = 10). Urinary exosomes were isolated and miRNA cargo was sequenced by Illumina-NextSeq-500.ResultsWe found that NC-AME subjects had lower cortisone (p < 0.0001), higher F/E ratio (p < 0.0001), lower serum potassium (p = 0.009) and higher FEK 24 h (p = 0.03) than controls. We found miR-204-5p (fold-change = 0.115; p 0.001) and miR-192-5p (fold-change = 0.246; p 0.03) are both significantly downregulated in NC-AME. miR-192-5p expression was correlated with PRA (r = 0.45; p 0.028) and miR-204-5p expression with SBP (r = − 0.48, p 0.027) and F/E ratio (r = − 0.48; p 0.026).ConclusionsThese findings could support a potential role of these miRNAs as regulators and novel biomarkers of the NC-AME phenotype.

Overview of Monogenic Forms of Hypertension Combined With Hypokalemia

“…Previously, a high ratio of urinary cortisol to cortisone (F/E) was considered a basis for AME diagnosis. Recent studies ( 36 , 37 ) show that serum F/E and urinary exosomes miRNA levels are more sensitive for the prediction of AME-II. In addition, it is necessary to distinguish the disease from those with acquired suppression of the activity of HSD11B2 by the ingestion of excessive liquorice or carbenoxolone ( 38 ).…”

Aldosterone and Renin Concentration Abnormally Elevated in a Cohort of Normotensive Pregnant Women

“…The samples were analyzed using the NS300 instrument (Malvern, UK) with the NanoSight NTA 3.0 Nanoparticle Tracking and Analysis software (Version Build 0064). The videos (two videos per sample) were processed and analyzed as previously described, which inform the mean, mode, and median particle size together with an estimated number of particles per mL of plasma [33].…”

“…sEVs shape and size was determined by transmission electron microscopy as described [33]. For this, 15 µL sEVs pellet was added onto a carbon-coated copper grid (300 mesh) for 1 min and stained with 2% uranyl acetate for 1 min.…”

Novel Metabolomic Profile of Subjects with Non-classic Apparent Mineralocorticoid Excess

“…All subjects in this study had a clinical record and physical examination that included age, height, weight, body mass index (BMI) and blood pressure (BP) 13 . BP measurements were obtained from the right arm at consecutive 5-minute intervals using an oscillometric method (Dinamap CARESCAPE V100, GE Healthcare, Medical Systems Information Technologies, Milwaukee, WI), with the subjects remaining in a seated position.…”

“…To date, the cause of NC-AME has not been elucidated. However, we recently determined that NC-AME could be associated with minor genetic defects (i.e., heterozygous pathogenic variant or polymorphisms) 9 or epigenetic modi cations such as miRNAs 13 . However, salt intake, glycyrrhetinic acid-like factors (GALFs) and environmental factors 5 have been hypothesized to be factors that deregulate the expression and activity of HSD11B2.…”