The Angiotensin II Type 2 Receptor, a Target for Protection and Regeneration of the Peripheral Nervous System?

Figure 1. Schematic representation of the renin-angiotensin system (RAS). Angiotensin (Ang) I is cleaved by angiotensin-converting enzyme (ACE) to Ang II which can be then cleaved to Ang III by aminopeptidase A, then further cleaved to Ang IV by aminopeptidase B. Ang I can also be cleaved by ACE2 to produce Ang (1–9) which can be cleaved into Ang (1–7) by ACE. Ang (1–7) can be directly generated from Ang II by ACE2. Ang (1–7) binds and activates the receptors Mas and Mas-related G protein-coupled receptor member D (MrgD), Ang IV binds to AT4R, Ang III activates AT1R and AT2R and Ang (1–9) directly activates AT2R. Functionally, it is possible to simplify the RAS into two distinctive pathways [12]. The first involves over-activation of AT1R by Ang II/Ang III, promoting cellular growth, vasoconstriction, fibrosis and inflammation. The second involves the interactions between AT2R and Ang II/Ang (1–9)/Ang III, but also Ang (1–7) and Mas/MrgD receptors, and Ang IV and AT4R, leading to vasodilatation and anti-proliferative, anti-fibrotic, anti-inflammatory effects.

Figure 2. Expression of AT2R in the sensory peripheral nervous system. According to the most recent immunohistochemistry study on the expression of AT2R in DRG and in the spinal cord of rat, AT2R would be expressed by almost all types of sensory neurons, though to different degrees [18]. Non-peptidergic C-nociceptors expressing IB4 are strongly stained for AT2R. Some small and medium DRG neurons co-expressed AT2R and trkA, a marker of nociceptive neurons (peptidergic C and Aδ neurons). The few large neurons which express AT2R are stained for NF200 and trkA, markers of Aα/β nociceptive neurons. Most ATR2+ neurons are also AT1R+. AT1R: angiotensin II type 1 receptor, AT2R: angiotensin II type 2 receptor, CGRP: calcitonin gene-related peptide, DRG: dorsal root ganglion, IB4: isolectin 4, NF200: neurofilament 200, SP: substance P, trkA: tropomyosin receptor kinase type A.

Figure 3. AT2R-mediated intracellular signaling pathways involved in neuronal cells. Several intracellular signaling pathways are associated with AT2R activation in neuronal cells leading to apoptosis via activation of the phosphatase MPK-1, neurite elongation via reorganization of the cytoskeleton, or neuronal differentiation in part via upregulation of growth-factors, depending on the cell type, the context, and the environment. To date, ATIP1 is identified as a partner of AT2R involved in intracellular signaling pathway and trafficking in neuronal cells. While the evidence of an ATIP/AT2R complex comes from experiments on central nervous system neurons, we could hypothesize that a similar system exists in PNS neurons. AT2R signaling may antagonize AT1R-mediated signaling by a direct heterodimerization between the two. As well, homodimerization of AT2R might result in ligand-independent signaling.