Serum Alpha-1-Acid Glycoprotein-1 and Urinary Extracellular Vesicle miR-21-5p as Potential Biomarkers of Primary Aldosteronism

Abstract

Primary aldosteronism (PA) is the most common cause of secondary hypertension and reaches a prevalence of 6-10%. PA is an endocrine disorder, currently identified as a broad-spectrum phenotype, spanning from normotension to hypertension. In this regard, several studies have made advances in the identification of mediators and novel biomarkers of PA as specific proteins, miRNAs, and lately, extracellular vesicles (EVs) and their cargo.AimTo evaluate lipocalins LCN2 and AGP1, and specific urinary EV miR-21-5p and Let-7i-5p as novel biomarkers for PA.Subjects and MethodsA cross-sectional study was performed in 41 adult subjects classified as normotensive controls (CTL), essential hypertensives (EH), and primary aldosteronism (PA) subjects, who were similar in gender, age, and BMI. Systolic (SBP) and diastolic (DBP) blood pressure, aldosterone, plasma renin activity (PRA), and aldosterone to renin ratio (ARR) were determined. Inflammatory parameters were defined as hs-C-reactive protein (hs-CRP), PAI-1, MMP9, IL6, LCN2, LCN2-MMP9, and AGP1. We isolated urinary EVs (uEVs) and measured two miRNA cargo miR-21-5p and Let-7i-5p by Taqman-qPCR. Statistical analyses as group comparisons were performed by Kruskall-Wallis, and discriminatory analyses by ROC curves were performed with SPSS v21 and Graphpad-Prism v9.ResultsPA and EH subjects have significantly higher SBP and DBP (p <0.05) than the control group. PA subjects have similar hs-CRP, PAI-1, IL-6, MMP9, LCN2, and LCN2-MMP9 but have higher levels of AGP1 (p <0.05) than the CTL&EH group. The concentration and size of uEVs and miRNA Let-7i-5p did not show any difference between groups. In PA, we found significantly lower levels of miR-21-5p than controls (p <0.05). AGP1 was associated with aldosterone, PRA, and ARR. ROC curves detected AUC for AGP1 of 0.90 (IC 95 [0.79 – 1.00], p <0.001), and combination of AGP1 and EV-miR-21-5p showed an AUC of 0.94 (IC 95 [0.85 – 1.00], p<0.001) to discriminate the PA condition from EH and controls.ConclusionSerum AGP1 protein was found to be increased, and miR-21-5p in uEVs was decreased in subjects classified as PA. Association of AGP1 with aldosterone, renin activity, and ARR, besides the high discriminatory capacity of AGP1 and uEV-miR-21-5p to identify the PA condition, place both as potential biomarkers of PA.

Proteomic analysis of urinary extracellular vesicles highlights specific signatures for patients with primary aldosteronism

“…Among the proteins resulting from the fold-change analysis of the EH vs PA comparison, we have found also A1AG1 (AGP1), a protein that is recently attracting attention as a potential biomarker for PA ( 12 , 33 ). A1AG1 is an acute-phase protein associated with inflammation, it has been suggested to indicate increased cardiovascular risk, and its upregulation in uEVs of PA patients may be a consequence of mineralocorticoid activation ( 12 ).…”

Analysis of the miRNA expression from the adipose tissue surrounding the adrenal neoplasia

“…This mRNA can interfere with cortisol and aldosterone syntheses binding on the untranslated region of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) genes ( 36 ). Previously, Carvajal et al ( 37 ) evaluated in PA several mediators and novel biomarkers of chronic inflammation; in a finding that compared normotensive subjects and patients with EH, PA showed higher serum alpha-1-acid glycoprotein-1 (AGP-1) protein [specifically related to aldosterone, renin levels, and aldosterone-to-renin ratio (ARR)] and decreased the expression of miR-21-5p. AGP-1 could be evaluated with a dual role, as a potential biomarker of PA and as a possible mediator of the tissue response to high aldosterone production.…”

“…AGP-1 could be evaluated with a dual role, as a potential biomarker of PA and as a possible mediator of the tissue response to high aldosterone production. The downregulation of miR-21-5p could affect the downstream target genes related to inflammation, interleukin-1β (IL-1 β) gene, and fibrotic processes ( 37 ). A study by Nakamura et al ( 38 ) demonstrated that CYP11B1, a steroidogenic enzyme, which converts deoxycorticosterone to corticosterone, was diffusely detected in the APA, and it could play a pivotal role in the tumor genesis.…”

Orosomucoid-1 Arises as a Shared Altered Protein in Two Models of Multiple Sclerosis

“…Orm1 was the only protein with significantly altered expression in each condition. The concentration of Orm proteins in the plasma increases in response to inflammatory stimuli (Baumann and Gauldie, 1990;Alam and Papaconstantinou, 1992;Wigmore et al, 1997;Luo et al, 2015), enabling it to carry out immunoregulatory functions and suggesting that Orm1 may serve as a potential biomarker in different diseases (Baraniuk et al, 2005;Luo et al, 2015;Zhou et al, 2016;Brink et al, 2019;Shu et al, 2020;Carvajal et al, 2021). Orm1 is a transport protein that plays a dual role in regulating inflammation, producing both anti-and pro-inflammatory effects (Taguchi et al, 2013;Smith and Waters, 2018).…”