{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T07:07:43Z","timestamp":1784099263059,"version":"3.55.0"},"reference-count":23,"publisher":"National Academy of Sciences","issue":"38","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,9,19]]},"abstract":"<jats:p>\n                    Frame-shift mutations within the C terminus of aquaporin 2 (AQP2) cause autosomal-dominant nephrogenic diabetes insipidus (AD-NDI). To identify the molecular mechanism(s) of this disease\n                    <jats:italic>in vivo<\/jats:italic>\n                    and to test possible therapeutic strategies, we generated a mutant AQP2 (763\u2013772 del) knockin mouse. Heterozygous knockin mice showed a severely impaired urine-concentrating ability. However, they were able to slightly increase urine osmolality after dehydration. This milder phenotype, when compared with autosomal-recessive NDI, is a feature of AD-NDI in humans, thus suggesting successful establishment of an AD-NDI mouse model. Immunofluorescence of collecting duct cells in the AD-NDI mouse revealed that the mutant AQP2 was missorted to the basolateral instead of apical plasma membrane. Furthermore, the mutant AQP2 formed a heterooligomer with wild-type AQP2 and showed a dominant-negative effect on the normal apical sorting of wild-type AQP2 even under dehydration. Using this knockin mouse, we tested several drugs for treatment of AD-NDI and found that rolipram, a phosphodiesterase 4 inhibitor, was able to increase urine osmolality. Phosphodiesterase inhibitors may thus be useful drugs for the treatment of AD-NDI. This animal model demonstrates that a mutant monomer gains a dominant-negative effect that reverses the normal polarized sorting of multimers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0602331103","type":"journal-article","created":{"date-parts":[[2006,9,12]],"date-time":"2006-09-12T22:25:03Z","timestamp":1158099903000},"page":"14217-14222","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":89,"title":["Pathogenesis and treatment of autosomal-dominant nephrogenic diabetes insipidus caused by an aquaporin 2 mutation"],"prefix":"10.1073","volume":"103","author":[{"given":"Eisei","family":"Sohara","sequence":"first","affiliation":[{"name":"*Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatemitsu","family":"Rai","sequence":"additional","affiliation":[{"name":"*Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Sen","family":"Yang","sequence":"additional","affiliation":[{"name":"*Department of Nephrology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosaku","family":"Nitta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Horita","sequence":"additional","affiliation":[{"name":"Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayuko","family":"Ohno","sequence":"additional","affiliation":[{"name":"Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawadacho, Shinjuku, Tokyo 162-8666, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Harada","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Traffic, Department of Molecular and Cellular Biology, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Shouwamachi, Maebashi, Gunma 371-8512, 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