title: AMPK Suppresses Connexin43 Expression in the Bladder and Ameliorates Voiding Dysfunction in Cyclophosphamide-induced Mouse Cystitis.
abstract: Bladder voiding dysfunction is closely related to local oxidation, inflammation, and enhanced channel activities. Given that the AMP-activated protein kinase (AMPK) has anti-oxidative, anti-inflammatory and channel-inhibiting properties, we examined whether and how AMPK affected bladder activity. AMPK activation in rat bladder smooth muscle cells (BSMCs) using three different AMPK agonists resulted in a decrease in connexin43 (Cx43) expression and function, which was associated with reduced CREB phosphorylation, Cx43 promoter activity and mRNA expression, but not Cx43 degradation. Downregulation of CREB with siRNA increased Cx43 expression. A functional analysis revealed that AMPK weakened BSMC contraction and bladder capacity. AMPK also counteracted the IL-1β- and TNFα-induced increase in Cx43 in BSMCs. In vivo administration of the AMPK agonist AICAR attenuated cyclophosphamide-initiated bladder oxidation, inflammation, Cx43 expression and voiding dysfunction. Further analysis comparing the responses of the wild-type (Cx43(+/+)) and heterozygous (Cx43(+/-)) Cx43 mice to cyclophosphamide revealed that the Cx43(+/-) mice retained a relatively normal micturition pattern compared to the Cx43(+/+) mice. Taken together, our results indicate that AMPK inhibits Cx43 in BSMCs and improves bladder activity under pathological conditions. We propose that strategies that target AMPK can be developed as novel therapeutic approaches for treating bladder dysfunction.
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.|Department of Urology, The 4th affiliated hospital of China Medical University, Shenyang, China.
authors.forename: Xiling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Jian
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.affiliation: Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chi
authors.affiliation: Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Mitsui
authors.affiliation: Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ihara
authors.affiliation: Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Sawada
authors.affiliation: Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kamiyama
authors.affiliation: Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Jianglin
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Urology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003520:Cyclophosphamide / Q000009:adverse effects; D003556:Cystitis / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051381:Rats
chemical_list: D018031:Connexin 43; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D018836:Inflammation Mediators; D003520:Cyclophosphamide; D055372:AMP-Activated Protein Kinases