**1. Aminopeptidases in the Renin–Angiotensin System**

The renin–angiotensin system (RAS) plays an essential role in blood pressure (BP) control, via vascular, renal, brain, and other mechanisms. Abnormalities in RAS activity may lead to the development of arterial hypertension and other cardiovascular and renal diseases. Blockade of this system is an effective therapeutic measure against numerous diseases, and RAS compounds have been found in the kidney, brain, and other tissues. Over recent years, our knowledge of the components of the RAS has increased, including numerous angiotensin peptides with diverse biological activities mediated by different receptor subtypes [1,2].

The enzymatic cascade of the RAS is depicted in Figure 1. It is initiated by angiotensinogen, an alfa 2 globulin of hepatic origin, which generates angiotensin I (AngI) through the enzymatic action of renin on the extreme amino-terminus. The decapeptide AngI is a substrate for angiotensin-converting enzyme (ACE), which splits the dipeptide His-Leu from the extreme carboxy-terminus to generate the octapeptide AngII [1], the major effector peptide of the RAS, which bind to two major receptors, AT1 and AT2, that generally oppose each other.

**Figure 1.** The renin–angiotensin system.

Action of glutamyl aminopeptidase (APA) on AngII removes the Asp residue N-terminus to generate the heptapeptide AngIII. AngIII can also be generated by an AngII-independent pathway via the nonapeptide [des-Asp1]AngI, produced from AngI by AspAP, which is converted to AngIII via ACE. APA also participates in the formation of Ang(1-7), which can also be transformed into Ang(2-7) through cleaving of the Asp-Arg bond.

In the extreme N-terminus, membrane alanyl aminopeptidase N (APN) removes Arg to give hexapeptide angiotensin IV (AngIV). AngIV is also transformed into Ang(3-7) by carboxypeptidase P (Carb-P) and propyl oligopeptidase through scission of the Pro-Phe carboxy-terminus.

ACE2 can also transform AngII into Ang(1-7) through hydrolysis of Phe by Carb-P or through scission of the dipeptide Phe-His from Ang(1-9) [1–4].

Aminopeptidase B (APB), also known as arginine aminopeptidase (Arg-AP), cleaves basic amino acids at the N-terminus. It participates in the conversion of AngIII to AngIV.

Although not part of the RAS, both neuropeptides oxytocin and vasopressin are cleaved at the N-terminus of cysteine next to tyrosine by cystinyl aminopeptidase (CAP), a rat homolog of insulin-regulated AP (IRAP) [5].

All these enzymes are globally called "angiotensinases" because they are responsible for the generation of systemic and local peptides (angiotensins) related to the regulation of BP and the excretion of sodium and water. These enzymes determine the proportions of bioactive compounds.

AngI is biologically inactive, but AngII and AngIII act as agonists for AT1 and AT2 receptors, thereby mediating pressor and dipsogenic effects [6,7]. AngIV has a low affinity for AT1 and AT2 receptors but high affinity and specificity for the AT4 receptor subtype. Interaction with the AT1 receptor subtype reduces the pressor effect of AngIV. A counterregulatory system to the AngII-AngIII/AT1 receptor system is composed of ACE2 and Ang(1-7), which activate the Mas receptor [6–8]. This system induces vasodilatory, antifibrotic, antihypertrophic, and antiproliferative effects.
