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These proteins are thought to form a signaling complex that can flux cations, including calcium. One of the earliest symptoms in ADPKD is a decline in the concentrating ability of the kidneys, occurring prior to cyst formation. We reasoned that hyperosmolality stimulates the polycystin complex, and that the loss of this function impairs water reabsorption. We found that hyperosmolality resulted in the phosphorylation of microtubule-associated protein 4 (MAP4) in a PC1-dependent manner, which then elicited ER-localized PC2 calcium signals. ER-localized PC2 hyperosmotic calcium signals were required for trafficking of the water channel aquaporin (AQP2). Precystic PC1-KO and PC2-KO murine kidneys had cytosol-localized AQP2 and diluted urine compared with their respective controls. Kidney tissue sections from ADPKD patients showed decreased AQP2 apical membrane localization in cystic and noncystic tubules. Our study demonstrates that osmolality is a physiological stimulus of the polycystin complex, and loss of polycystin osmosensing results in impaired water reabsorption via AQP2. This likely contributes to the declined concentrating ability of the kidneys and high circulating vasopressin levels in patients with ADPKD.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.186290","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T19:46:40Z","timestamp":1754423200000},"source":"Crossref","is-referenced-by-count":1,"title":["Hyperosmotic stimuli activate polycystin proteins to aid in urine concentration"],"prefix":"10.1172","volume":"10","author":[{"given":"Karla M.","family":"M\u00e1rquez-Nogueras","sequence":"first","affiliation":[{"name":"Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryne M.","family":"Knutila","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, 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