Visceral hypersensitivity is the main driver of abdominal pain in relation to irritable bowel syndrome (IBS), which may be associated with various factors (Pusceddu and Gareau, 2018; Sengupta, 2009). Recently, considerable attention has been given to the role of enteric glial cells (EGCs) and the secretory mediators of the enteric nervous system (ENS) in the visceral hypersensitivity response to IBS.

EGCs are a prominent component of the ENS. Upon alteration of the gastrointestinal environment, EGCs are activated, calcium-binding protein S100β and glial fibrillary acidic protein (GFAP) expression is upregulated, and substance P (SP) is released and expressed to participate in visceral hypersensitivity (Grubišić and Gulbransen, 2017; Wang et al., 2016). This state of EGCs is referred to as the reactive EGC phenotype. In addition, calcitonin gene-related peptide (CGRP) and transient receptor potential vanilloid 1 (TRPV1) are also closely associated with visceral hypersensitivity in relation to IBS (Akbar et al., 2008; Shi et al., 2015).

Considerable evidence supports the concept of a local tissue or cellular renin–angiotensin–aldosterone system (RAAS) (Karnik et al., 2015; Obukhov et al., 2020). Some studies have shown that the local RAAS can be involved in inflammation and pain (Bali et al., 2014; Karnik et al., 2015). Ang II mainly binds with high affinity to Ang II type 1 (AT1) receptor to generate inflammatory responses and reactive oxygen species (Xu et al., 2017) and participates in nociception (Hegazy et al., 2020a). Ang II has been shown to co-localize with AT1 receptor, SP, CGRP, and TRPV1 in the dorsal root ganglion (DRG) (Anand et al., 2015; Patil et al., 2010), which provides strong evidence supporting the involvement of Ang II binding to AT1 receptor in nociception. AT1 receptor activation in spinal dorsal horn neurons and astrocytes causes activation of the mitogen-activated protein kinase (MAPK) pathway, which is involved in spinal pain transmission (Nemoto, 2018; Ogata et al., 2016). AT1 receptor blockers or angiotensin-converting enzyme 1 (ACE1) inhibitors, on the other hand, can prevent and relieve pain (Bali et al., 2014; Marques-Lopes et al., 2009).

Losartan (Los) is a selective AT1 receptor blocker with significant anti-inflammatory effects (Kalynovska et al., 2020; Yamamoto et al., 2015). Whereas inflammation may contribute to the induction and maintenance of pain, studies have shown that Los may attenuate colonic injury by inhibiting pro-inflammatory cytokine production in the colonic mucosa (Shi et al., 2016). Several studies have demonstrated the presence of Ang II and AT1 receptor in the ENS, that Ang II excites neurons in the myenteric and submucosal plexuses (Wang et al., 2005). However, the role of the ACE1/Ang II/AT1 receptor axis in EGC activation and visceral hypersensitivity in IBS is unclear.

Therefore, we hypothesized that the ACE1/Ang II/AT1 receptor axis may interact with EGCs to participate in IBS visceral hypersensitivity and that Los may improve IBS visceral hypersensitivity by modulating the ACE1/Ang II/AT1 receptor axis to inhibit EGC activation. We explored the mechanism involving Los intervention in an acetic acid enema-induced IBS rat model and lipopolysaccharide (LPS)-induced EGCs in vitro experiments.