Abstract
Lower urinary tract symptoms (LUTS) include storage, voiding and post-micturition symptoms, featuring many urological diseases. Storage symptoms are the most frequent among these and associated with overactive bladder and non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS). Gap junction, a key regulator of hyperactive conditions in the bladder, has been reported to be involved in pathological bladder inflammation. Here we report involvement of gap junction in the etiology of storage symptoms in bladder inflammation. In this study, cyclophosphamide-induced cystitis was adapted as a model of bladder inflammation. Cyclophosphamide-treated mice showed typical storage symptoms including increased urinary frequency and reduced bladder capacity, with concurrent up-regulation of connexin 43 (GJA1), one of the major gap junction proteins in the bladder. In isometric tension study, bladder smooth muscle strips taken from the treated mice showed more pronounced spontaneous contraction than controls, which was attenuated by carbenoxolone, a gap junction inhibitor. In voiding behavior studies, the storage symptoms in the treated mice characterized by frequent voiding were alleviated by 18α-glycyrrhetinic acid, another gap junction inhibitor. These results demonstrate that cyclophosphamide-induced mouse model of cystitis shows clinical storage symptoms related with bladder inflammation and that gap junction in the bladder may be a key molecule of these storage symptoms. Therefore, gap junction in the bladder might be an alternative therapeutic target for storage symptoms in bladder inflammation.
Highlights
Lower urinary tract symptoms (LUTS) are common in all populations, with a reported prevalence of approximately 60% [1]
The microarray data discussed in this publication have been deposited in NCBI’s Gene Expression Omnibus (Edgar et al, 2002) and are accessible through GEO Series accession number GSE55986
Microarray results showed that expression of Gja1, which we previously proposed as the key gene related to bladder function [16,17,18], was elevated 1.40 fold in the bladders of CYP-treated mice
Summary
Lower urinary tract symptoms (LUTS) are common in all populations, with a reported prevalence of approximately 60% [1]. Because of the difficulty in excluding all pathological disorders, clinically diagnosed OAB could involve misdiagnosed diseases of non-bacterial bladder inflammation such as interstitial cystitis/bladder pain syndrome (IC/BPS). Anti-muscarinic agents, which target neurogenic mechanisms, have been reported to be not effective for storage symptoms in diseases of bladder inflammation such as chronic pelvic pain syndrome and IC/BPS [14,15]. These data suggest that bladder inflammation could contribute to non-neurogenic mechanisms causing storage symptoms, but not neurogenic ones
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