{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:35:53Z","timestamp":1778272553411,"version":"3.51.4"},"reference-count":57,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T00:00:00Z","timestamp":1708128000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>High concentrations of urinary calcium counteract vasopressin action via the activation of the Calcium\u2010Sensing Receptor (CaSR) expressed in the luminal membrane of the collecting duct cells, which impairs the trafficking of aquaporin\u20102 (AQP2). In line with these findings, we provide evidence that, with respect to wild\u2010type mice, CaSR knock\u2010in (KI) mice mimicking autosomal dominant hypocalcaemia, display\u00a0a significant decrease in the total content of AQP2 associated with significantly higher levels of AQP2 phosphorylation at Ser261, a phosphorylation site involved in AQP2 degradation. Interestingly, KI mice also had significantly higher levels of phosphorylated p38MAPK, a downstream effector of CaSR and known to phosphorylate AQP2 at Ser261. Moreover, ATF1 phosphorylated at Ser63, a transcription factor downstream of p38MAPK, was significantly higher in KI. In addition, KI mice had significantly higher levels of AQP2\u2010targeting miRNA137 consistent with a post\u2010transcriptional downregulation of AQP2. <jats:italic>In vivo<\/jats:italic> treatment of KI mice with the calcilytic JTT\u2010305, a CaSR antagonist, increased AQP2 expression and reduced AQP2\u2010targeting miRNA137 levels in KI mice.\u00a0Together, these results provide direct evidence for a critical role of CaSR in impairing both short\u2010term vasopressin response by increasing AQP2\u2010pS261, as well as AQP2 abundance, via the p38MAPK\u2010ATF1\u2010miR137 pathway.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15951-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Calcium\u2010Sensing Receptor (CaSR) activating mutations are the main cause of autosomal dominant hypocalcaemia (ADH) characterized by inappropriate renal calcium excretion leading to hypocalcaemia and hypercalciuria. Current treatments of ADH patients with parathyroid hormone, although improving hypocalcaemia, do not improve hypercalciuria or nephrocalcinosis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p><jats:italic>In vivo<\/jats:italic> treatment with calcilytic JTT\u2010305\/MK\u20105442 ameliorates most of the ADH phenotypes of the CaSR knock\u2010in mice including hypercalciuria or nephrocalcinosis and reverses the downregulation of the vasopressin\u2010sensitive aquaporin\u20102 (AQP2) expression, providing direct evidence for a critical role of CaSR in impairing vasopressin response.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The beneficial effect of calcilytic in reducing the risk of renal calcification may occur in a parathyroid hormone\u2010independent action through vasopressin\u2010dependent inhibition of cAMP synthesis in the thick ascending limb and in the collecting duct.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The amelioration of most of the abnormalities in calcium metabolism including hypercalciuria, renal calcification, and AQP2\u2010mediated osmotic water reabsorption makes calcilytic a good candidate as a novel therapeutic agent for ADH.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp284233","type":"journal-article","created":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T18:24:35Z","timestamp":1708194275000},"page":"3207-3224","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>In vivo<\/i> treatment with calcilytic of CaSR knock\u2010in mice ameliorates renal phenotype reversing downregulation of the vasopressin\u2010AQP2 pathway"],"prefix":"10.1113","volume":"602","author":[{"given":"Marianna","family":"Ranieri","sequence":"first","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Environment University of Bari  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