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Vasopressin 2 receptor activation increases cAMP and activates PKA, which, in turn, phosphorylates aquaporin (AQP)2, triggering apical membrane accumulation, increased collecting duct permeability, and water reabsorption. We used single-minded homolog 1 ( Sim1)-Cre recombinase-mediated expression of a dominant negative PKA regulatory subunit (RI\u03b1B) to disrupt kinase activity in vivo and assess the role of PKA in fluid homeostasis. RI\u03b1B expression gave rise to marked polydipsia and polyuria; however, neither hypothalamic Avp mRNA expression nor urinary AVP levels were attenuated, indicating a primary physiological effect on the kidney. RI\u03b1B mice displayed a marked deficit in urinary concentrating ability and greatly reduced levels of AQP2 and phospho-AQP2. Dehydration induced Aqp2 mRNA in the kidney of both control and RI\u03b1B-expressing mice, but AQP2 protein levels were still reduced in RI\u03b1B-expressing mutants, and mice were unable to fully concentrate their urine and conserve water. We conclude that partial PKA inhibition in the kidney leads to posttranslational effects that reduce AQP2 protein levels and interfere with apical membrane localization. These findings demonstrate a distinct physiological role for PKA signaling in both short- and long-term regulation of AQP2 and characterize a novel mouse model of diabetes insipidus.<\/jats:p>","DOI":"10.1152\/ajprenal.00222.2014","type":"journal-article","created":{"date-parts":[[2015,1,14]],"date-time":"2015-01-14T01:50:01Z","timestamp":1421200201000},"page":"F627-F638","source":"Crossref","is-referenced-by-count":14,"title":["Expression of a dominant negative PKA mutation in the kidney elicits a diabetes insipidus phenotype"],"prefix":"10.1152","volume":"308","author":[{"given":"Merle L.","family":"Gilbert","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linghai","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Washington, Seattle, Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. 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