**1. Introduction**

High blood pressure, leading to cardiovascular and cerebrovascular disorders, is the principal cause of morbidity and mortality worldwide [1–3]. The renin-angiotensin system (RAS) is a major regulator of cardiovascular function and pharmaceutical compounds targeting the RAS are frontline treatments to control high blood pressure [4, 5]. In addition, lifestyle risk factors such as obesity, insulin resistance, high alcohol and salt intake and ageing promote the development of hypertension through epigenetic mechanisms [6–9]. These mechanisms have attracted attention because of their reversibility by environmental and lifestyle modi-

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**Figure 1.** The renin-angiotensin system (RAS) and its components. This schematic depicts angiotensin ligands, receptors and the main enzymes involved; other peptidases and cathepsins also participate although to a lesser extent. All of the components of the RAS are present in the brain. RAS has two main axes: the pressor axis (tending towards an increase in blood pressure) comprising Ang II, ACE and AT1Rs and the counter-regulatory axis comprising Ang(1–7), ACE2 and MasR. Angiotensinogen is a substrate for renin to produce angiotensin I (Ang I), which is the inactive precursor of all angiotensin peptides. Conversion of Ang I to its most active ligand in the pressor axis, angiotensin II (Ang II), results from ACE-mediated hydrolysis [22]. Ang II is then sequentially converted to angiotensin III (Ang III) and angiotensin IV (Ang IV) by aminopeptidase A (APA) and aminopeptidase N (APN) respectively, which can be further cleaved by carboxypeptidase P (CP) and prolyl oligopeptidase (PO) to form angiotensin 3–7 (Ang3–7). Alternatively, Ang II can be converted, via the counter-regulatory axis to angiotensin 1–7 (Ang1–7) by carboxypeptidase P (CP) or ACE2, while both angiotensin A and Ang1–7 can be converted to alamandine by an ACE-mediated decarboxylation reaction [22–27]. Notably, angiotensin ligands acting on AT4R (also called insulin-regulated aminopeptidase (IRAP)) can have agonist or antagonist effects depending on whether or not they bind in the IRAP peptidase domain.

fications, making them important in the detection and treatment of multifactorial diseases such as hypertension [7, 10].

Some of those epigenetic modifications are mediated by miRNAs, defined as single-stranded, non-coding RNA sequences approximately 21–23 nucleotides in length, expressed under physiological and pathological conditions [11, 12]. Deletion of complexes involved in miRNA biogenesis resulted in deleterious and non-viable phenotypes, highlighting their necessary involvement in the cellular development and differentiation [13, 14]. To date, 28,645 miRNAs have been reported in miRbase, a widely used resource for miRNA cataloging and nomenclature [15]. As epigenetic regulators of gene expression, functions of miRNAs include RNA degradation, inhibition of protein expression, regulation of methylation and histone modification on DNA [12, 14, 16]. miRNAs perform these functions by complementary base pairing to the target mRNAs through a seed-pairing region of 6–8 nucleotides at the 5′ end of the miRNA. They also interact with other non-coding RNAs and mediate proteome remodelling. Non-coding RNAs represent 98% of the genome, comprising transfer and ribosomal RNA, small nuclear (snRNA) and nucleolar RNA (snoRNA), small interference RNA (siRNA), Piwiinteracting RNA (piRNA) and long non-coding RNAs (lncRNA) [14, 17, 18].

Dysregulation of miRNAs is associated with cancer, cardiovascular and neurodegenerative disorders. The RAS, with important signalling roles in numerous organs and regulatory pathways and being subject to miRNA-mediated remodelling, is a potential factor in many disorders. Thus, the presence of miRNAs that have the capacity to shift the balance between prominent and deleterious functions of the RAS to beneficial roles is interesting, particularly new advances in methods that allow the detection of circulating miRNAs. Exosomes and their role in cellular transport provide a source for miRNA profiling and the presence of miR-NAs in the peripheral circulation suggests that they work in an autocrine, paracrine and also endocrine manner, allowing widespread distribution of miRNAs through the entire body. Therefore, screening of miRNA in biological fluids like a serum and cerebrospinal fluid is relevant for an understanding of normal function as well as pathophysiology with a view to potential novel treatments for the disease.

The discovery of local independent but interacting RAS systems, including the brain, which also interacts with systemic RAS [3], has helped to change the original view that the RAS was solely an endocrine system important in regulating blood pressure, electrolytic homeostasis, vascular injury and repair [19]. The brain RAS discussed here (**Figure 1**) is multifunctional including regulation of cerebral blood flow, electrolyte balance, neurotransmitters, learning and memory, many of which may be associated with certain neurological disorders [20, 21].
