**1. Introduction**

In its classical view, RAS was defined as an endocrine system involved in blood pressure regulation and body electrolyte balance. However, RAS is now considered a "ubiquitous" system that is expressed locally in various tissues and exerts multiple paracrine/autocrine e ffects involved in tissue physiology and homeostasis [1]. Indeed, RAS plays key roles in cellular growth, proliferation, di fferentiation, migration, and apoptosis, in addition to extracellular matrix (ECM) remodeling and inflammation [2].

Alterations in RAS expression were shown to be involved in multiple diseases including atherosclerosis, cardiac hypertrophy, type 2 diabetes, and renal fibrosis [2–4]. On the other hand, RAS-blocking agents, such as angiotensin converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs), have been shown to be e ffective in the managemen<sup>t</sup> of hypertension-related cardiovascular diseases and end-organ damage [5]. Therefore, it is necessary to know the components of RAS, their tissue-specific expression, and how they may change under pathological conditions. In this review, we discuss classical and novel components of RAS, their role in local tissue physiology, and their changes under specific pathological conditions. A better understanding of local tissue RAS expression and regulation will help achieve more tissue- and condition-specific treatments.

#### **2. An Overview of RAS**

In its classical view, RAS includes successive enzymatic reactions resulting in the conversion of the "inactive" substrate angiotensinogen (AGT), into the active peptide angiotensin II (Ang-II) which binds to its specific membrane receptors and elicits cellular e ffects [2] (Figure 1 and Table 1). AGT is a glycoprotein continuously produced by the liver. In addition, it is di fferentially expressed in multiple

other tissues, including heart, blood vessels, kidneys, and adipose tissue [2]. AGT production can be induced by several stimuli, including inflammation, insulin, estrogen, glucocorticoids, thyroid hormone, and Ang-II [6].

**Figure 1.** RAS components. Colors correspond to different arms of RAS: Orange, Angiotensin-I; pink, Angiotensin-(1–12); red, Angiotensin-II; green, Angiotensin-(1–7); Blue, Angiotensin III/VI; violet, Alamandine. Proteins are represented by the corresponding official gene symbols. The figure was adapted from Nehme et al. 2015 [7].

In the plasma, AGT is converted into the decapeptide angiotensin-I (1–10) (Ang-I) by renin (Figure 1 and Table 1), a tightly regulated enzyme produced by the juxtaglomerular cells (JG) [8]. In fact, this step is considered the rate limiting step of Ang-II release in the circulation [8]. Renin is synthesized as an inactive enzyme that is cleaved by microsomes to produce prorenin [9]. Prorenin is then either released as inactive precursor or converted by a variety of proteases into active intracellular renin that is stored in granules of the JG cells. Active renin is released into the circulation by JG cells via an exocytic process and upon a stimulus [8,10] by different mechanisms including Ang-II negative feedback [10].

Ang-I is further processed by angiotensin-converting enzyme (ACE), a membrane-bound exopeptidase, to release the vasoactive octapeptide angiotensin II (1–8) (Ang-II) (Figure 1 and Table 1). Besides Ang-II production, ACE can degrade a number of vasodilating peptides including Ang-(1–7), bradykinin, and kallikrein, thus playing a central role as a vasopressor enzyme [2,8]. Moreover, ACE can activate cellular signaling when bound to its inhibitors (ACEIs) and bradykinin, leading to increased ACE and COX2 production [11].


**Table 1.** Extended renin-angiotensin-aldosterone system components.

\* Classical RAS components.

Ang-II is a biologically active peptide that mediates its e ffects via the angiotensin-II type 1 receptor (AT1R) [12] (Figure 1). Ang-II was originally known as a circulating hormone that regulates blood pressure and electrolyte balance by acting on vascular contraction, aldosterone secretion, renal sodium handling, sympathetic activity, and vasopressin release [2]. However, molecular studies have shown that AT1R activation can exert long-term genetic e ffects, in addition to rapid short term e ffects at the cellular level [13]. Like most other GPCRs, AT1R undergoes rapid desensitization and internalization after agonist stimulation to avoid extensive chronic activation [2].

One of the major e ffects of Ang-II is the stimulation of aldosterone synthase, CYP11B2, expression in the adrenal cortex [14] (Figure 1 and Table 1). Aldosterone has emerged as an essential regulator of blood pressure in mammals, and has been associated with a variety of diseases in humans [15]. Aldosterone acts in a variety of tissues through its mineralocorticoid receptor (MR) to influence extracellular fluid volume, blood pressure and salt exchange, but may also lead to pathological consequences, mainly tissue fibrosis and oxidative stress [16].

#### **3. The Concept of Tissue RAS**

Several lines of evidence support the concept of extended RAS that includes multiple synonymous enzymatic pathways for the generation of di fferent angiotensin peptides which exert their e ffects in a tissue- and condition-specific manner [17]. These pathways may explain the dual role of RAS as not only a circulating hormone, but also a tissue-specific regulatory system serving autocrine, paracrine, and even intracrine functions.

The first demonstration of the presence of a local tissue RAS was in 1971, where a renin-like activity was found in the brain of dogs and which was independent of renin found in the kidney and plasma [18]. This finding was then supported by the identification of Ang-I-like peptides in dog brain with variable molecular weights [19]. Since then, local angiotensin pathways and their physiological importance were elucidated in di fferent tissues including the heart, blood vessels, kidney, brain, adipose tissue, adrenal gland, pancreas, liver, reproductive system, lymphatic tissue, placenta and the eye (Table 2) [2,20,21]. In these tissues, local RAS acts independently from systemic RAS in a paracrine and autocrine manner, but may still interact with systemic RAS to exert endocrine e ffects [2]. A study conducted by Lau et al. showed a local angiotensin-generating system in the exocrine pancreas. Their data showed the existence of an islet angiotensin-generating system that has an important role in physiological regulation of glucose-induced insulin secretion [22]. In addition, recent studies have reported the expression of renin and angiotensinogen genes and identified their products at many local tissue sites, which further supports the concept of multiple tissues synthesizing RAS components [23]. In fact, multiple studies have described tissue RAS and reported its role in various tissues such as cardiac, vascular and renal tissues, which have the majority of ACE in the body. It seems that tissue RAS has long-term e ffects on cardiovascular function and structure, while its alteration can cause pathologic conditions [24].


