{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T21:49:47Z","timestamp":1778276987666,"version":"3.51.4"},"reference-count":66,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2018,1,5]],"date-time":"2018-01-05T00:00:00Z","timestamp":1515110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003981","name":"Agenzia Spaziale Italiana","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003981","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:p>\n                    High concentrations of urinary calcium counteract vasopressin action via the activation of the calcium\u2010sensing receptor (CaSR) that is expressed in the luminal membrane of collecting duct cells, which impairs the trafficking of aquaporin\u20102 (AQP2). Pendrin\/NaCl cotransporter double\u2010knockout (dKO) mice display significant calcium wasting and develop severe volume depletion, despite increased circulating vasopressin levels. We hypothesized that the CaSR\u2010mediated impairment of AQP2 expression\/trafficking underlies vasopressin resistance in dKO mice. Compared with wild\u2010type mice, in renal inner medulla, dKO mice had reduced total AQP2 sensitive to proteasome inhibitors, higher levels of AQP2\u2010pS261, ubiquitinated AQP2, and p38\u2010MAPK, an enzyme that is activated by CaSR signaling and known to phosphorylate AQP2 at Ser261. CaSR inhibition with the calcilytic NPS2143 reversed these effects, which indicates that CaSR mediates the up\u2010regulation of AQP2\u2010pS261, ubiquitination, and degradation. Of note, dKO mice demonstrated significantly higher AQP2\u2010targeting miRNA\u2010137 that was reduced upon CaSR inhibition, supporting a critical role for CaSR in the down\u2010regulation of AQP2 expression. Our data indicate that CaSR signaling reduces AQP2 abundance both\n                    <jats:italic>via<\/jats:italic>\n                    AQP2\u2010targeting miRNA\u2010137 and the p38\u2010MAPK\/AQP2\u2010pS261\/ubiquitination\/proteasomal axis. These effects may contribute to the reduced renal concentrating ability that has been observed in dKO mice and underscore a physiologic mechanism of the CaSR\u2010dependent regulation of AQP2 abundance\n                    <jats:italic>via<\/jats:italic>\n                    a novel microRNA pathway.\u2014 Ranieri, M., Zahedi, K., Tamma, G., Centrone, M., Di Mise, A., Soleimani, M., Valenti, G. CaSR signaling down\u2010regulates AQP2 expression\n                    <jats:italic>via<\/jats:italic>\n                    a novel microRNA pathway in pendrin and NaCl cotransporter knockout mice.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    32, 2148\u20132159 (2018).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700412rr","type":"journal-article","created":{"date-parts":[[2017,12,6]],"date-time":"2017-12-06T10:30:18Z","timestamp":1512556218000},"page":"2148-2159","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["CaSR signaling down\u2010regulates AQP2 expression\n                    <i>via<\/i>\n                    a novel microRNA pathway in pendrin and NaCl cotransporter knockout mice"],"prefix":"10.1096","volume":"32","author":[{"given":"Marianna","family":"Ranieri","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnologies, and Biopharmaceutics University of Bari Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamyar","family":"Zahedi","sequence":"additional","affiliation":[{"name":"Research Services Veterans Affairs Medical Center Cincinnati Ohio USA"},{"name":"Department of Medicine University of Cincinnati Cincinnati Ohio USA"},{"name":"Center on Genetics of Transport and Epithelial Biology University of Cincinnati Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grazia","family":"Tamma","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies, and Biopharmaceutics University of Bari Bari Italy"},{"name":"Istituto Nazionale di Biostrutture e Biosistemi Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariangela","family":"Centrone","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies, and Biopharmaceutics University of Bari Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annarita","family":"Di Mise","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies, and Biopharmaceutics University of Bari Bari Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoocher","family":"Soleimani","sequence":"additional","affiliation":[{"name":"Research Services Veterans Affairs Medical Center Cincinnati Ohio USA"},{"name":"Department of Medicine University of Cincinnati Cincinnati Ohio USA"},{"name":"Center on Genetics of Transport and Epithelial Biology University of Cincinnati Cincinnati Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanna","family":"Valenti","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies, and Biopharmaceutics University of Bari Bari Italy"},{"name":"Centre of Excellence in Comparative Genomics University of Bari Bari Italy"},{"name":"Istituto Nazionale di Biostrutture e Biosistemi Rome Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2018,1,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00037.2002"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00147.2002"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00205.2002"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000356639"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.0148.2001"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.64.081501.155847"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00011.2004"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.V142538"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.ndt.a027081"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI113847"},{"key":"e_1_2_8_12_1","first-page":"F546","article-title":"Thiazidesensitive sodium chloride cotransport in early distal tubule","volume":"253","author":"Ellison D. 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