A map and new directions for the (pro)renin receptor in the brain: focus on “A role of the (pro)renin receptor in neuronal cell differentiation”

Abstract

OVER THE LAST FEW DECADES, THE renin-angiotensin system (RAS) has seen the discovery of several new members, both in the periphery and in the central nervous system (CNS), including substrates, enzymes, and receptors, and one may wonder why textbooks are still teaching an oversimplified and outdated version of this system. Far from being the straightforward cascade containing one substrate [angiotensinogen], two peptides, [angiotensin (ANG) I, ANG II], two enzymes [renin, angiotensin-converting enzyme (ACE)] and one receptor (AT 1 ), the RAS currently includes nearly a dozen of ANG fragments, some active and some inactive, more than two dozen peptidases, and at least six different receptors. Moreover, the RAS now consists of several axes upstream and downstream of the classical cascade. While sometimes, these newcomers are considered to be "missing links," more often they are viewed with skepticism. In addition, it is now well accepted that local RASs are present in most organs and tissues, including but not limited to the heart, kidney, vasculature, adipose tissue, pancreas, and brain, and they are involved in the local regulation of these tissues.Since its first description by Ganten et al. (3), in the early 1970s, the brain RAS has been the subject of controversy and debate. Is ANG II generated in the brain or does it travel from the periphery? Is ANG III the real ligand for the AT 1 receptor in the CNS? Is Mas the receptor for ANG (1-7)? Is there a non-AT 1 , non-AT 2 receptor? What is the binding site for ANG IV? Although some of these questions have been answered, for example, it is now well accepted that ANG II in the CNS can be generated locally, and it also can enter the brain via the circumventricular organs, other claims still spark debates.Probably the oldest controversy for the brain RAS concerns the presence of renin in the CNS. Because renin levels in the brain are usually low and likely not homogenous throughout the various nuclei, they have been difficult to assess. As a consequence, over the years, different theories have emerged, generally involving alternate pathways for the synthesis of ANG II. Accordingly, evidence has shown that the octapeptide could be produced via tonin, chymase, cathepsins, and other peptidases (see Ref. 11 for a full list). One of the latest possibilities for a renin-independent synthesis of ANG II involves the recently discovered ANG (1-12) peptide (12), which could eventually be transformed successively into ANG (1-10), then ANG II, through the action of ACE. However, as recently reviewed by Grobe et al. (4), genetic studies argue against renin-independent pathways, essentially because of the lack of phenotype in transgenic animals overexpressing angiotensinogen in the brain and support the presence of this enzyme in the CNS (1, 7). In addition, evidence has shown the existence of a nonsecreted intracellular form of the enzyme, renin-b, which is functional in the brain of rodents and humans (5).A new piece of the puzzle is presented in this issue (2) by Dr. Genevieve...

Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin system

“…The discovery of a (pro)renin receptor ([P]RR) and the introduction of renin inhibitors have also brought (pro)renin back into the spotlight [7]. Far from being a straightforward cascade containing one substrate (AGT), two proteases (renin and ACE), two peptides (Ang I and Ang II) and one receptor (AT1), the RAS currently consists of several axes upstream and downstream of the classical cascade, which include more than two dozen peptidases, nearly a dozen Ang fragments and at least six different receptors [8]. Here, we review three critical proteases (ACE, ACE2 and renin) within and beyond the RAS and thus intend to find new connections between natural plant and/or food resources and the RAS.…”

The effects of para-chloromercuribenzoic acid and different oxidative and sulfhydryl agents on a novel, non-AT1, non-AT2 angiotensin binding site identified as neurolysin

“…Newly identified components (pro)renin receptor [12] [13], ACE2 [13,14], Mas protein (putative receptor for angiotensin (1–7) [15], and the AT 4 receptor for angiotensin IV [16,17] have revolutionized our understanding of the functionality of the RAS. Components of the RAS have been found in a wide range of tissues and organs with classic cardiovascular functions as well as novel functions [18,19], In the brain the RAS also acts in regions associated with novel functions, such as cell differentiation, memory, and neurogenesis [7,10,20,21]. Newly discovered roles for the brain RAS in pathogenesis include the formation of intracranial aneurysms [22] mental retardation [23,24] and a role in epilepsy [24,25].…”

Involvement of the Brain (Pro)renin Receptor in Cardiovascular Homeostasis

“…PRR plays a dual role in the regulation of RAS activity: it binds prorenin/renin to facilitate angiotensin II formation locally; and the binding initiates an intracellular signaling cascade which is similar to those associated with angiotensin II mediated increases in pressor, proliferative, and fibrotic actions4, 6. These observations, coupled with recent data that PRR is highly expressed in cardiovascular-relevant brain regions and afftect neurons in vitro 7,8, have led us to propose the following hypothesis: brain PRR is involved in the regulation of central cardiovascular function and its dysregulation may contribute to hypertension.…”