Acyloxyacyl hydrolase regulates voiding activity

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 non voiding 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 Cif was elevated in Barrington's nucleus of A0A11deficient mice. We had previously identified aryl hydrocarbon receptor (AhR) and peroxisome proliferator-activated receptor-'y as transcriptional regulators of Cif, and conditional knockout of AhR or peroxisorne proliferator-activated receptor--y in Crf -expressing cells restored normal voiding in AOAH-deficient mice. Finally, an AhR antagonist improved voiding in A0A11-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.