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

Abstract

Preclinical evidence, accumulated over the past decade, indicates that the angiotensin II type 2 receptor (AT2R) stimulation exerts significant neuroprotective effects in various animal models of neuronal injury, notably in the central nervous system. While the atypical G protein-coupled receptor superfamily nature of AT2R and its related signaling are still under investigation, pharmacological studies have shown that stimulation of AT2R leads to neuritogenesis in vitro and in vivo. In this review, we focus on the potential neuroprotective and neuroregenerative roles of AT2R specifically in the peripheral nervous system (PNS). The first section describes the evidence for AT2R expression in the PNS and highlights current controversies concerning the cellular distribution of the receptor. The second section focuses on AT2R signaling implicated in neuronal survival and in neurite outgrowth. The following sections review the relatively few preclinical studies highlighting the putative neuroprotective and neuroregenerative effects of AT2R stimulation in the context of peripheral neuropathy.

Angiotensin II Induces Differentiation of Human Neuroblastoma Cells by Increasing MAP2 and ROS Levels

“…The high abundance of this receptor is also transiently expressed in rodent fetus, suggesting that Ang II could have a role in the AT2 receptor during development and cell differentiation [ 36 ]. For example, activation of this receptor can induce neurite formation and neuronal differentiation in vitro from rat pheochromocytoma cell line PC12W and fetal rat neurons [ 9 , 37 ] , revin [ 38 ]. In humans, mutations of the AT2 receptor have been found in female or male patients with mental retardation and have been implicated in brain development and maturation [ 39 , 40 ].…”

Shedding Light on the Pharmacological Interactions between μ-Opioid Analgesics and Angiotensin Receptor Modulators: A New Option for Treating Chronic Pain

“…Components of the renin-angiotensin system (RAS) have been previously reviewed or discussed extensively [19,24,[58][59][60][61][62][63][64]. Nevertheless, the main findings are briefly summarized here for an overview.…”

“…Accumulating evidence has proven that drugs affecting the renin-angiotensin system can modulate pain transmission [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Recent studies have also shown that drugs mimic or antagonize angiotensin type 1 and 2 (AT1R and AT2R) receptor-mediated actions do produce a beneficial analgesic effect in rodent models of chronic pain types [17,20,22,28,29,[35][36][37][38].…”

“…Recent studies have also shown that drugs mimic or antagonize angiotensin type 1 and 2 (AT1R and AT2R) receptor-mediated actions do produce a beneficial analgesic effect in rodent models of chronic pain types [17,20,22,28,29,[35][36][37][38]. The analgesic effect of ligands affecting angiotensin receptors in neuropathic pain is explained by the contribution of these receptors to neuroregeneration and neuroprotectionpartially by reducing neural inflammatory processes [18,24,37,[39][40][41]. Nevertheless, much remains unclear regarding the role and clinical utility of these receptors in analgesia.…”

Ramipril Alleviates Oxaliplatin-Induced Acute Pain Syndrome in Mice

“…Most of the RAS components are known to be expressed into the sensory nervous system, tending to demonstrate the presence of a local RAS in the peripheral nervous system ( Bessaguet et al, 2016 ). Various preclinical studies have highlighted the involvement of RAS modulation by the use of ACE inhibitors or angiotensin receptor blockers, in neuroprotection and pain control ( Gallinat et al, 1998 ; Lucius et al, 1998 ; Patil et al, 2010 ; Pavel et al, 2013 ; Kaur et al, 2015 ; Yuksel et al, 2015 ; Bessaguet et al, 2017 ; Danigo et al, 2021 ). Modulation of RAS was neuroprotective in rodent models of traumatic nerve injury like chronic constriction injury and sciatic nerve transection, as well as in rodent models of diabetic neuropathy or toxic neuropathy (CIPN) ( Oltman et al, 2008 ; Kaur et al, 2015 ; Yuksel et al, 2015 ; Bessaguet et al, 2017 ; Kim et al, 2019 ).…”