Regulación de la enzima 11 beta hidroxiesteroide deshidrogenasa tipo 2 [11ß-HSD2] por miRNA y su asociación con hipertensión arterial

Abstract

Classical apparent mineralocorticoid excess (AME) is a rare recessive disorder, caused by 11β-HSD2 deficiency. AME manifests as low-renin pediatric hypertension, hypokalemia and high cortisol/cortisone (F/E) ratio. The study of mild AME cases (NC-AME) requires more clinical suspicion. It has been suggested that the partial deficit of 11βHSD2 can be negatively regulated by microRNAs. miRNA expression can be evaluated in exosomes found in biofluids, which are nanovesicles released from different cell types and though as potential reporters of local metabolic conditions. Aim: To evaluate the activity of 11βHSD2 and its epigenetic regulation by miRNA, in urinary exosomes, through a clinical, biochemical and molecular study model. Subjects and Methods: We recruited 127 adolescents and adults. Subjects with secondary hypertension were excluded. Serum F/E was measured by HPLC/MS-MS. Renal, vascular and inflammatory damage were evaluated with validated biomarkers. Sequencing of HSD11B2 gene was performed in all subjects. RNA was isolated from spot urinary exosomes by ultracentrifugation and analyzed by Nanosight NS300. The miRNAs expression were assayed by Taqman-qPCR. The associations are analyzed by Spearman and comparisons were performed Mann-Whitney test (p<0,05). Results: F/E ratio was positively associated with systolic Blood Pressure (SBP), microalbuminuria and high sensitive c reactive protein (hsCRP). Serum cortisone correlated with MR activation parameters even when adjusted for age, BMI and sex: lower cortisone with higher potassium excretion (partial r= -0.29, p=0.002) and with lower plasma renin activity (PRA, partial r= 0.29, p=0.001). Consistently, we identified, 9/127 subjects (7.1%) with high F/E ratio (First quartile) and low cortisone (Last quartile), suggestive of NC-AME.These subjects had higher SBP (mmHg): 141.4 ± 25.7 vs 127.3 ± 18.1 p=0.03; lower PRA (ng/L*s): 0.36 ± 0.19 vs 0.64 ± 0.47, p<0.0001) and greater potassium excretion, microalbuminuria, hs-CRP and PAI-1. We only found in 2/9 NC-AME subjects heterozygous mutations in HSD11B2 gene. The urinary exosomes concentration was lower in subjects with 11βHSD2-PD vs controls (6.8x1011 [3.4x1011 - 7.8x1011] vs 7.5 x1011 [5.3x1011 - 9.8x1011] particles/ml; p<0.05) and the expression of miR-488 in urinary exosomes is higher in subjects with NCAME vs controls (p = 0.01). Conclusion: We describe a new spectrum of partial deficiency of 11β-HSD2 (NC-AME), which represent 7.1% of the population. The miRNAs could have a role in the negative regulation of 11βHSD2 expression and could be evaluated in urinary exosomes, which would be potential biomarkers of local metabolism at the renal level.