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Cells from ADPKD cysts have a reduced resting cytosolic calcium [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and increased cAMP levels. CaSR plays an essential role in regulating calcium homeostasis. Its activation is associated with [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> increase and cAMP decrease, making CaSR a possible therapeutic target. Human conditionally immortalized Proximal Tubular Epithelial cells (ciPTEC) with stable knockdown of PKD1 (ciPTEC-PC1KD) and ciPTEC generated from an ADPKD1 patient (ciPTEC-PC1Pt) were used as experimental tools. CaSR functional expression was confirmed by studies showing that the calcimimetic NPS-R568 induced a significant increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> in ciPTEC-PC1KD and ciPTEC-PC1Pt. Resting [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> were significantly lower in ciPTEC-PC1KD with respect to ciPTECwt, confirming calcium dysregulation. As in native cyst cells, significantly higher cAMP levels and mTOR activity were found in ciPTEC-PC1KD compared to ciPTECwt. Of note, NPS-R568 treatment significantly reduced intracellular cAMP and mTOR activity in ciPTEC-PC1KD and ciPTEC-PC1Pt. To conclude, we demonstrated that selective CaSR activation in human ciPTEC carrying PKD1 mutation increases [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>, reduces intracellular cAMP and mTOR activity, reversing the principal dysregulations considered the most proximal events in ADPKD pathogenesis, making CaSR a possible candidate as therapeutic target.<\/jats:p>","DOI":"10.1038\/s41598-018-23732-5","type":"journal-article","created":{"date-parts":[[2018,4,4]],"date-time":"2018-04-04T03:21:38Z","timestamp":1522812098000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Activation of Calcium-Sensing Receptor increases intracellular calcium and decreases cAMP and mTOR in PKD1 deficient cells"],"prefix":"10.1038","volume":"8","author":[{"given":"Annarita","family":"Di Mise","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazia","family":"Tamma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Ranieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Centrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lambertus","family":"van den Heuvel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djalila","family":"Mekahli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena N.","family":"Levtchenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Valenti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,4,9]]},"reference":[{"key":"23732_CR1","doi-asserted-by":"publisher","first-page":"2315","DOI":"10.1172\/JCI72272","volume":"124","author":"PC Harris","year":"2014","unstructured":"Harris, P. 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