Acyloxyacyl hydrolase regulates voiding activity

Abstract

Corticotropin-releasing factor (CRF) regulates diverse physiological functions, including bladder control. We recently reported that Crf expression is under genetic control of Aoah, the locus encoding acyloxyacyl hydrolase (AOAH), suggesting that AOAH may also modulate voiding. Here, we examined the role of AOAH in bladder function. AOAH-deficient mice exhibited enlarged bladders relative to wild-type mice and had decreased voiding frequency and increased void volumes. AOAH-deficient mice had increased nonvoiding contractions and increased peak voiding pressure in awake cystometry. AOAH-deficient mice also exhibited increased bladder permeability and higher neuronal firing rates of bladder afferents in response to stretch. In wild-type mice, AOAH was expressed in bladder projecting neurons and colocalized in CRF-expressing neurons in Barrington’s nucleus, an important brain area for voiding behavior, and Crf was elevated in Barrington’s nucleus of AOAH-deficient mice. We had previously identified aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-γ as transcriptional regulators of Crf, and conditional knockout of AhR or peroxisome proliferator-activated receptor-γ in Crf-expressing cells restored normal voiding in AOAH-deficient mice. Finally, an AhR antagonist improved voiding in AOAH-deficient mice. Together, these data demonstrate that AOAH regulates bladder function and that the AOAH- Crf axis is a therapeutic target for treating voiding dysfunction.

Acyloxyacyl Hydrolase is a Host Determinant of Gut Microbiome-Mediated Pelvic Pain

“…Our previous studies show that AOAH-deficient mice mimic symptoms and comorbidities of IC/BPS [7, 13, 14]. Here we show that the pelvic pain phenotype and anxiety/depressive-like behavior can be regulated by microbiota (Figs 7 and 8).…”

“…2), suggesting that AOAH effects on gut gene expression lie elsewhere. Indeed, we previously reported that AOAH is a genetic regulator of the locus encoding corticotropin-releasing factor (CRF), in brain sites mediating bladder and stress responses where AOAH deficiency leads to increased Crf expression and stress responses [13, 14]. CRF alters gut function at multiple levels (reviewed in [50, 51]).…”

“…Transepithelial electrical resistance. Cecum and bladder permeability were measured as transepithelial electrical resistance (TEER) as previously described for bladders in Aguiniga et al., 2020 [13]. Excised organs were bisected and immediately placed in Ringer's solution at room temperature.…”

“…AOAH-deficient mice also have voiding dysfunction [13], and display rodent correlates of anxious/depressive behaviors [14]. Expressed along the bladder-brain axis, AOAH functions as an arachidonyl acyl transferase, and AOAH-deficient mice exhibit defects in central nervous system (CNS) arachidonic acid homeostasis and increased accumulation of PGE2, contributing to pelvic pain [15].…”

“…Previous studies in our lab demonstrated that mice deficient for AOAH spontaneously develop pelvic allodynia consistent with pelvic pain and exhibit heightened response in induced pelvic pain models [7]. AOAH-deficient mice also have voiding dysfunction [13], and display rodent correlates of anxious/depressive behaviors [14]. Expressed along the bladder-brain axis, AOAH functions as an arachidonyl acyl transferase, and AOAH-deficient mice exhibit defects in central nervous system (CNS) arachidonic acid homeostasis and increased accumulation of PGE2, contributing to pelvic pain [15].…”