The objective of this study was to analyze the relationship of polymorphisms of the angiotensin II AT1 receptor gene with microalbuminuria in a group of young adults with essential hypertension. Essential hypertensives, less than 50 years old, never previously treated with antihypertensive drugs, and in absence of diabetes mellitus were included. Office blood pressure (BP), 24-h ambulatory BP monitoring, urinary albumin excretion (UAE) measurements, and DNA analysis were performed. Polymorphisms of the angiotensin II AT1-receptor gene (A1166C and C573T) were studied by polymerase chain reaction and single-strand conformation polymorphism techniques. One hundred eighty-three patients, 49 (27%) microalbuminurics, were included. Office and ambulatory BP values were significantly higher in the microalbuminuria group. No differences in the presence of microalbuminuria were observed among the genotypes of either A1166C or C573T polymorphisms of the angiotensin II receptor AT1 gene, or in the allele frequency of the A1166C or the C573T polymorphism. LogUAE was significantly different among genotypes of the C573T polymorphism [CC 1.30(1.15-1.45), CT 1.14(1.00-1.28), and TT 0.94(0.68-1.20), P < .05]. Both office and ambulatory blood pressure and the TT/C573T genotype were independently related to logUAE, and, at the same BP values, UAE was lower in subjects with this genotype. We have found that the C573T polymorphism is on linkage disequilibrium with A1166C, as the 573T allele is closely linked to the presence of the 1166A allele, but not vice versa. Haplotype analysis among subjects with the AA genotype for the A1166C polymorphism confirms the influence of the TT genotype of the C573T polymorphism on the UAE in hypertensives. The C573T polymorphism of the angiotensin II receptor AT1 gene seems to be a genetic protective factor for UAE in a population of essential hypertensives.

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Objective: In a previous work we established an exosomal miRNA signature associated to urinary albumin excretion (UAE) in hypertension, which included microRNA (miRNA) miR-26a, and obtaining cell signaling (MAPK, calcium, p53), TGF-ß and VEGF pathways as the most regulated biological processes. The aim of this work was to validate the exosomal miR-26a changes and its potential association with TGF-ß in human podocytes. Design and method: This prospective study analysed the miR-26a levels in 52 hypertensive patients, 24 with UAE (162,8 ± 168.2 mg/g creatinine; mean age 52.7 ± 8.4 years) and 28 normoalbuminuric (mean age 54.5 ± 5.6 years). Exosomes were isolated by differential ultracentrifugation from urine and plasma and miRNA levels were calculated by qRT-PCR. Urinary levels of TGF-ß1 were quantified by ELISA. Finally, human podocytes cultures were stimulated with recombinant human TGF-ß1 at several concentrations (5 ng/mL, 10 ng/mL and 15 ng/mL) for up 24 h to assess miR-26a changes in exosomal and cellular fractions. Results: We found a decrease in the levels of miR-26-5p in plasma and urinary exosomes of patients con increased UAE (p < 0.05 and p < 0.01, respectively). In addition, miR-26a-5p correlated inversely with UAE levels, both in urinary and plasma exosomes (r = -0.49, p < 0.01; r = -0.53, p < 0.01). Our patients also showed a significant increase in urinary levels of TGF-ß1 (2-fold increase, p < 0.05) in hypertensive patients with UAE. Finally, we analysed the effect in vitro of TGF-ß1 stress. Significant changes in scaffolding of podocytes, such as an increase of vimentin levels, has been also observed. Finally, significant down-regulated miR-26a expression in exosomes from podocytes after TGF-ß1 stimulation (5 – 15 ng / mL): 2.23, 1.96 and 1.7-fold decrease, with p < 0.001 and p < 0.05, respectively. No significant changes were obtained at intracellular level. Conclusions: Our results show that miR-26a-5p is decreased in urinary and plasma exosomes of microalbuminuric patients. In addition, exosomal miR-26a podocyte release is associated with TGF-ß1 pathway, key molecule in the development and maintenance structure of the glomerular filtration barrier and fibrosis.