title: Altered detrusor gap junction communications induce storage symptoms in bladder inflammation: a mouse cyclophosphamide-induced model of cystitis.
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.
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Okinami
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nishikawa
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Negoro
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sugino
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshimura
authors.affiliation: Department of Urology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kanematsu
authors.affiliation: Department of Cell Physiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Hashitani
authors.affiliation: Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects* / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D018031:Connexin 43 / Q000378:metabolism; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000494:pharmacology; D003556:Cystitis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D017629:Gap Junctions / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018031:Connexin 43; C543076:GJA1 protein, mouse; D003520:Cyclophosphamide
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