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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-1\u03b2- and TNF\u03b1-induced increase in Cx43 in BSMCs. <jats:italic>In vivo<\/jats:italic> 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 (<jats:italic>Cx43<\/jats:italic><jats:sup>+\/+<\/jats:sup>) and heterozygous (<jats:italic>Cx43<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup>) Cx43 mice to cyclophosphamide revealed that the <jats:italic>Cx43<\/jats:italic><jats:sup>+\/\u2212<\/jats:sup> mice retained a relatively normal micturition pattern compared to the <jats:italic>Cx43<\/jats:italic><jats:sup>+\/+<\/jats:sup> 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.<\/jats:p>","DOI":"10.1038\/srep19708","type":"journal-article","created":{"date-parts":[[2016,1,25]],"date-time":"2016-01-25T12:19:10Z","timestamp":1453724350000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["AMPK Suppresses Connexin43 Expression in the Bladder and Ameliorates Voiding Dysfunction in Cyclophosphamide-induced Mouse Cystitis"],"prefix":"10.1038","volume":"6","author":[{"given":"Xiling","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiko","family":"Mitsui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Ihara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norifumi","family":"Sawada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Kamiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianglin","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Takeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,1,25]]},"reference":[{"key":"BFsrep19708_CR1","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1056\/NEJMra032662","volume":"350","author":"JG Ouslander","year":"2004","unstructured":"Ouslander, J. 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