FIGURE 17–2 Major physiologic inputs to renin release and proposed integration with signaling pathways in the juxtaglomerular cell. AC, adenylyl cyclase; ANG II, angiotensin II; ANP, atrial natriuretic peptide; cGK, protein kinase G; DAG, diacylglycerol; ER, endoplasmic reticulum; GC-A, particulate guanylyl cyclase; IP3, inositol trisphosphate; NE, norepinephrine; NO, nitric oxide; PDE, phosphodiesterase; PKA, protein kinase A; PLC, phospholipase C; sGC, soluble guanylyl cyclase. (Adapted, with permission, from Castrop H et al: Physiology of kidney renin. Physiol Rev 2010;90:607.) converting enzyme (Figure 17–1). ANG I may also be acted on by plasma or tissue aminopeptidases to form [des-Asp1]angiotensin I; this in turn is converted to [des-Asp1]angiotensin II (commonly known as angiotensin III) by converting enzyme.
Converting Enzyme (Angiotensin-Converting Enzyme [ACE], Peptidyl Dipeptidase, Kininase II)
Converting enzyme is a dipeptidyl carboxypeptidase with two active sites that catalyzes the cleavage of dipeptides from the carboxyl terminal of certain peptides. Its most important substrates are ANG I, which it converts to ANG II, and bradykinin, which it inactivates (see Kinins, below). It also cleaves enkephalins and substance P, but the physiologic significance of these effects has not been established. The action of converting enzyme is prevented by a penultimate prolyl residue in the substrate, and ANG II is therefore not hydrolyzed by converting enzyme. Converting enzyme is distributed widely in the body. In most organs, converting enzyme is located on the luminal surface of vascular endothelial cells and is thus in close contact with the circulation.
A homolog of converting enzyme known as ACE2 is highly expressed in vascular endothelial cells of the kidneys, heart, and testes. Unlike converting enzyme, ACE2 has only one active site and functions as a carboxypeptidase rather than a dipeptidyl carboxypeptidase. It removes a single amino acid from the C-terminal of ANG I forming ANG 1-9 (Figure 17–3), which is inactive but is
FIGURE 17–3 The renin-angiotensin system showing the established system (black) and more recently discovered pathways involving the (pro)renin receptor (red) and ANG 1-7 (blue). (Adapted, with permission, from Castrop H et al: Physiology of kidney renin. Physiol Rev 2010;90:607.) converted to ANG 1-7 by ACE. ACE2 also converts ANG II to ANG 1-7. ANG 1-7 has vasodilator activity, apparently mediated by the orphan heterotrimeric guanine nucleotide-binding protein-coupled receptor (Mas receptor). This vasodilation may serve to counteract the vasoconstrictor activity of ANG II. ACE2 also differs from ACE in that it does not hydrolyze bradykinin and is not inhibited by converting enzyme inhibitors (see below).
ANG II, which has a plasma half-life of 15–60 seconds, is removed from the circulation by a variety of peptidases collectively referred to as angiotensinase. It is metabolized during passage through most vascular beds (a notable exception being the lung). Most metabolites of ANG II are biologically inactive, but the initial product of aminopeptidase action—[des-Asp1]angiotensin II or angiotensin III—retains some biologic activity.