{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T08:07:59Z","timestamp":1770710879851,"version":"3.49.0"},"reference-count":53,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T00:00:00Z","timestamp":1622592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["project number 387509280, SFB 1350 (project A3)"],"award-info":[{"award-number":["project number 387509280, SFB 1350 (project A3)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss of function of PKD1 (polycystin 1) or PKD2 (polycystin 2). The Ca2+-activated Cl\u2212 channel TMEM16A has a central role in ADPKD. Expression and function of TMEM16A is upregulated in ADPKD which causes enhanced intracellular Ca2+ signaling, cell proliferation, and ion secretion. We analyzed kidneys from Pkd1 knockout mice and found a more pronounced phenotype in males compared to females, despite similar levels of expression for renal tubular TMEM16A. Cell proliferation, which is known to be enhanced with loss of Pkd1\u2212\/\u2212, was larger in male when compared to female Pkd1\u2212\/\u2212 cells. This was paralleled by higher basal intracellular Ca2+ concentrations in primary renal epithelial cells isolated from Pkd1\u2212\/\u2212 males. The results suggest enhanced intracellular Ca2+ levels contributing to augmented cell proliferation and cyst development in male kidneys. Enhanced resting Ca2+ also caused larger basal chloride currents in male primary cells, as detected in patch clamp recordings. Incubation of mouse primary cells, mCCDcl1 collecting duct cells or M1 collecting duct cells with dihydrotestosterone (DHT) enhanced basal Ca2+ levels and increased basal and ATP-stimulated TMEM16A chloride currents. Taken together, the more severe cystic phenotype in males is likely to be caused by enhanced cell proliferation, possibly due to enhanced basal and ATP-induced intracellular Ca2+ levels, leading to enhanced TMEM16A currents. Augmented Ca2+ signaling is possibly due to enhanced expression of Ca2+ transporting\/regulating proteins.<\/jats:p>","DOI":"10.3390\/ijms22116019","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T10:38:39Z","timestamp":1622630319000},"page":"6019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Gender-Dependent Phenotype in Polycystic Kidney Disease Is Determined by Differential Intracellular Ca2+ Signals"],"prefix":"10.3390","volume":"22","author":[{"given":"Khaoula","family":"Talbi","sequence":"first","affiliation":[{"name":"Physiological Institute, University of Regensburg, University Street 31, D-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1349-7605","authenticated-orcid":false,"given":"In\u00eas","family":"Cabrita","sequence":"additional","affiliation":[{"name":"Physiological Institute, University of Regensburg, University Street 31, D-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-5363","authenticated-orcid":false,"given":"Rainer","family":"Schreiber","sequence":"additional","affiliation":[{"name":"Physiological Institute, University of Regensburg, University Street 31, D-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6222-4593","authenticated-orcid":false,"given":"Karl","family":"Kunzelmann","sequence":"additional","affiliation":[{"name":"Physiological Institute, University of Regensburg, University Street 31, D-93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1038\/ki.1992.195","article-title":"Factors affecting the progression of renal disease in autosomal-dominant polycystic kidney disease","volume":"41","author":"Gabow","year":"1992","journal-title":"Kidney Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0272-6386(12)80179-X","article-title":"End-stage renal failure appears earlier in men than in women with polycystic kidney disease","volume":"24","author":"Stewart","year":"1994","journal-title":"Am. 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