It is now more than a century since Tigerstedt and Bergman first described renin as a substance from rabbit kidney extracts that increased blood pressure when injected into other recipient rabbits, although it was another 40 years before the significance of this discovery was appreciated. The number of publications discussing this system was relatively few until the mid-twentieth century. However, the number of references listed in PubMed increased exponentially between 1966 and 2007, thus making any formal review a cumbersome task.
The renin-angiotensin system (RAS) is a coordinated hormonal cascade that regulates fluid and electrolyte balance, arterial pressure, and renal development. It is recognized as playing a major role in cardiovascular, renal, and adrenal function [1,2]. In the classical view of the RAS, angiotensin (Ang) II, the biologically active octapeptide, is generated by a two-step enzymatic process in which its precursor, the inactive decapeptide Ang I, is cleaved from angiotensinogen by renin. Mature active renin is a glycosylated aspartyl protease secreted by the renal juxtaglomerular granular epitheloid cells from an exocytic process through both regulated and constitutive pathways. It is synthesized in the cells as an inactive form, prorenin, and activated by cleavage of an N-terminal prosegment of 43 amino acids.
The second step of Ang II synthesis is the removal of the C-terminal dipeptide of Ang I by an angiotensin-converting enzyme (ACE), a zinc dipeptidyl carboxypeptidase with two catalytic sites, which exists in both a soluble and membrane-bound form [3]. Angiotensin-converting enzyme has broad substrate in vitro and in vivo specificity [3]. For instance, in vivo it cleaves and thus inactivates bradykinin—a vasodilator and natriuretic peptide [3]—substance P [3], and also N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), a hemoregulatory peptide [4]. Therefore, as a major enzyme implicated in cardiovascular and renal physiology, ACE generates a potent vasoconstrictor and antinatriuretic peptide, Ang II, while simultaneously degrading a potent vasodilator and natriuretic peptide, bradykinin. The reaction of renin to angiotensinogen in plasma is the rate-limiting step of the RAS [5], whereas ACE appears to have no limiting influence on the systemic generation of Ang II. Once generated, Ang II binds to its receptors to activate intracellular signals; it is also rapidly cleaved within seconds by other enzymes, such as angiotensinases, into other shorter Ang-related peptides [Ang III, Ang (1-7), and Ang (3-8)] [1]. The biological functions of Ang III are well known. Although Ang (1-7) and Ang (3-8) are biologically active, their functions in vivo have not been fully elucidated. The majority of the effects of Ang II—vascular smooth muscle cell contraction and pressor response, aldosterone secretion, inhibition of renin release (negative feedback loop), renal sodium reabsorption, vasopressin secretion, dispogenic responses, generation of growth-promoting cytokines, free-oxygen radicals, and fibrosis mediators in tissues—are mediated by the AT1 receptor, a 7-transmembrane G-protein-coupled receptor [1]. Ang II also binds another 7-transmembrane G-protein-coupled receptor, the Ang II type 2 receptor (AT2R), whose functions remain controversial, depending on cell type, developmental stage, or pathophysiological state [6].
This view of the RAS has been expanded by additional findings. First, besides the circulating RAS, numerous studies have proved the importance of a local tissue RAS in the kidney, brain, heart, blood vessels, and adrenal glands in mediating diverse physiological functions [2]. Second, alternative non-ACE-dependent pathways of Ang II generation, such as chymase [7] and chymostatin-sensitive Ang II–generating enzyme (CAGE) [8], and new enzymes, such as the zinc metallocarboxypeptidase ACE2, have been described. Angiotensin-converting enzyme 2 hydrolyzes Ang I to Ang (1-9), Ang II to Ang (1-7), bradykinin to des-Arg⁹-bradykinin, and other substrates in vitro, but its functions in vivo have yet to be clarified [9,10]. Third, besides the AT1 and AT2 receptors, other receptors (AT4) and other signaling pathways have been described [11]. Finally, the discovery of the prorenin/renin receptor has given renin and prorenin a direct biological role in stimulating intracellular pathways independently of Ang II [12,13]. Besides being a systemic circulating system, locally active tissue-RAS was described in the kidney, adrenal glands, and brain.
Kai Kappert and Thomas Unger focus on the physiology of the RAS, its role in hypertension, and the pathophysiological impact of Ang II, the effector peptide in the RAS, on various tissues. They discuss the results of the major clinical trials, which have investigated the effects of different drug classes that target distinct components of the RAS, especially at the level of the ACE, AT1 receptor, and aldosterone receptor. Finally, they provide the most recent data concerning the new class of RAS blocker (direct renin inhibitors), approved for the treatment of hypertension, which inhibits the system at its first and rate-limiting step.
In 110 years, the knowledge of the RAS system has tremendously increased and in the last 30-year blockade the RAS, with ACE1 inhibitors and AT1 receptor blockers, has become one of the most successful therapeutic approaches in medicine. That said, Kappert and Unger remind the reader that “the book on RAS and its importance for blood pressure control and for a variety of cardiovascular and noncardiovascular diseases is far from being closed.”

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