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With a view toward possible use for treatment of patients with X\u2010linked nephrogenic diabetes insipidus (<jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content>) due to hemizygous mutations in the V2 vasopressin receptor, this study sought to determine the effect of roflumilast on aquaporin\u20102 (<jats:styled-content style=\"fixed-case\">AQP<\/jats:styled-content>2) phosphorylation,<jats:styled-content style=\"fixed-case\">AQP<\/jats:styled-content>2 trafficking, and water permeability in the rat inner medullary collecting duct (<jats:styled-content style=\"fixed-case\">IMCD<\/jats:styled-content>). In the presence of the vasopressin analog<jats:styled-content style=\"fixed-case\">dDAVP<\/jats:styled-content>(0.1\u00a0nmol\/L), both roflumilast and its active metabolite roflumilast<jats:italic>N<\/jats:italic>\u2010oxide (<jats:styled-content style=\"fixed-case\">RNO<\/jats:styled-content>) significantly increased phosphorylation at S256, S264, and S269, and decreased phosphorylation at S261 (immunoblotting) in<jats:styled-content style=\"fixed-case\">IMCD<\/jats:styled-content>suspensions in a dose\u2010dependent manner (3\u20133000\u00a0nmol\/L). Another commonly used phosphodiesterase inhibitor,<jats:styled-content style=\"fixed-case\">IBMX<\/jats:styled-content>, affected phosphorylation only at the highest concentration in this range. However, neither roflumilast nor<jats:styled-content style=\"fixed-case\">RNO<\/jats:styled-content>had an effect on<jats:styled-content style=\"fixed-case\">AQP<\/jats:styled-content>2 phosphorylation in the absence of vasopressin. Furthermore, roflumilast alone did not increase<jats:styled-content style=\"fixed-case\">AQP<\/jats:styled-content>2 trafficking to the plasma membrane (immunofluorescence) or increase water permeability in freshly microdissected perfused<jats:styled-content style=\"fixed-case\">IMCD<\/jats:styled-content>segments. We conclude that roflumilast can be used to enhance vasopressin's action on<jats:styled-content style=\"fixed-case\">AQP<\/jats:styled-content>2 activity in the renal collecting duct, but has no detectable effect in the absence of vasopressin. These findings suggest that roflumilast may not have a beneficial effect in X\u2010linked<jats:styled-content style=\"fixed-case\">NDI<\/jats:styled-content>, but could find useful application in acquired NDI.<\/jats:p>","DOI":"10.14814\/phy2.13121","type":"journal-article","created":{"date-parts":[[2017,1,21]],"date-time":"2017-01-21T01:25:45Z","timestamp":1484961945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Roflumilast and aquaporin\u20102 regulation in rat renal inner medullary collecting duct"],"prefix":"10.14814","volume":"5","author":[{"given":"Ezigbobiara N.","family":"Umejiego","sequence":"first","affiliation":[{"name":"Epithelial Systems Biology Laboratory Systems Biology Center NHLBI National Institutes of Health Bethesda Maryland 20892\u20101603"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Renal Division Department of Medicine Emory University Atlanta Georgia 30322"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Knepper","sequence":"additional","affiliation":[{"name":"Epithelial Systems Biology Laboratory Systems Biology Center NHLBI National Institutes of Health Bethesda Maryland 20892\u20101603"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung\u2010Lin","family":"Chou","sequence":"additional","affiliation":[{"name":"Epithelial Systems Biology Laboratory Systems Biology Center NHLBI National Institutes of Health Bethesda Maryland 20892\u20101603"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,1,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01869401"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000439065"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00307.2003"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00170.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1995.75.4.725"},{"key":"e_1_2_7_7_1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0026-895X(25)09714-7","article-title":"Multiple cyclic nucleotide phosphodiesterases","volume":"46","author":"Beavo J. 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