The AT2 receptor has a structure and affinity for ANG II similar to those of the AT1 receptor. In contrast, however, stimulation of AT2 receptors causes vasodilation that may serve to counteract the vasoconstriction resulting from AT1 receptor stimulation. AT2 receptor-induced vasodilation appears to be nitric oxide-dependent and may involve the bradykinin B2 receptor-nitric oxide-cGMP pathway. AT2 receptors are present at high density in all tissues during fetal development, and may play an important role in regulating cellular differentiation and organ development by virtue of their high abundance in fetal mesenchymal tissues. AT2 expression declines rapidly to an undetectable level in many tissues after birth, but low levels remain in the heart, adrenal gland, kidney, brain, and reproductive tissues.
Up-regulation occurs in some disease states including heart failure and myocardial infarction. In animal studies, activation of AT2 receptors has been reported to produce anti-inflammatory, anti-proliferative, antihypertrophic, antifibrotic, proapoptotic, and vasodilatory effects. These effects could help to counterbalance the detrimental effects of excessive ANG II mediated via AT1 receptors, and thereby protect against the progression of organ damage.
For many years, prorenin was considered to be an inactive precursor of renin, with no receptor or function of its own, despite its high levels in the circulation. However, a novel receptor has been described. This receptor binds both renin and prorenin and is therefore referred to as the (pro)renin receptor. It is a ubiquitously expressed 350-amino acid protein with a single transmembrane domain that binds prorenin to a large N-terminal extracellular domain.
When prorenin binds to the (pro)renin receptor, the prorenin undergoes a conformational change and becomes enzymatically active without cleavage of the prosegment. This is referred to as nonproteolytic to distinguish it from the proteolytic activation with prosegment removal that occurs in the kidney. Binding of prorenin to the receptor activates intracellular signaling pathways that differ depending on the cell type. For example, in mesangial and vascular smooth muscle cells, prorenin binding activates MAP kinases and expression of profibrotic molecules. Thus, elevated prorenin levels (as occur, for example, in diabetes mellitus) might have adverse effects via angiotensin-dependent and -independent pathways (Figure 17–3).
Renin inhibitors such as aliskiren (see below) do not block (pro)renin-induced signaling. However, a synthetic peptide named handle region peptide (HRP), which consists of the amino acid sequence corresponding to the “handle” region of the prorenin prosegment, has been synthesized and shown to competitively inhibit binding of prorenin to the (pro)renin receptor. HRP has been reported to have beneficial effects in the kidneys of diabetic rats. A newer putative (pro)renin receptor antagonist, PRO20, which corresponds to the first 20 amino acids of the prosegment of mouse prorenin, has been reported to lower blood pressure in an animal model of hypertension.
Note that the concentration of prorenin required to activate (pro)renin receptors is very high, much higher than that occurring under physiologic conditions.
In view of the importance of the renin-angiotensin system in cardiovascular disease, considerable effort has been directed to developing drugs that inhibit it. A wide variety of agents that block the formation or action of ANG II is now available. Some of these drugs block renin release, but most inhibit the enzymatic action of renin, inhibit the conversion of ANG I to ANG II (ACE inhibitors), or block angiotensin AT1 receptors (angiotensin receptor blockers [ARBs]).