Endocrine Abstracts

Hypertension is the most important risk factor in the development of cerebrovascular diseases including vascular cognitive impairment (VCI). Aldosterone is a key regulator of blood pressure, acting via the mineralocorticoid receptor (MR) in the kidney to promote sodium/water reabsorption. Elevated aldosterone, as in primary aldosteronism (PA) is a risk factor for cerebrovascular disease. In addition to its traditional role, the MR is expressed throughout the brain and vasculature, with potential as a dual target in VCI. The MR is partially regulated by non-coding microRNAs, which bind the 3’ untranslated region of genes for repression. MicroRNAs are packaged within extracellular vesicles (EVs), which can be manipulated therapeutically. This project seeks to deliver MR-specific microRNAs with therapeutic benefits in VCI. Using a combination of predictive and validated databases, 74 microRNAs were identified as binding the MR-3’UTR. This included miR-19a-3p and miR-124-3p, highlighted in a prior review of circulating microRNAs in stroke. Data from the previous ENSAT-HT study measured 20 MR-specific microRNAs in healthy, primary hypertensive and PA individuals (1). Levels of 4 MR-specific microRNAs were significantly elevated in PA plasma compared to normotensive/primary hypertensive individuals, including a 4-fold increase in miR-19a-3p. Validation of microRNA binding was performed by dual luciferase reporter assay and manipulation with precursor microRNAs. MR binding of miR-19a-3p and miR-124-3p was confirmed, with a significant decrease in reporter expression. EVs were loaded with precursor miR-19a-3p or miR-124-3p via electroporation. MicroRNA levels of miR-124-3p show a significant 4.5-fold increase in rat neuronal cells following 6-hour incubation with pre-miR-124-3p loaded EVs. MicroRNAs miR-19a-3p and miR-124-3p are promising candidates for targeting the MR. Future studies will assess neuroprotective effects in models of VCI.1) Reel PS, Reel S, Van Kralingen JC, et al. Machine learning for classification of hypertension subtypes using multi-omics: A multi-centre, retrospective, data-driven study. EBioMedicine; 2022.