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Enhanced proliferation and transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and Ca<jats:sup>2+<\/jats:sup>-activated TMEM16A Cl<jats:sup>\u2212<\/jats:sup> channels is thought to cause an increase in cyst volume. Recent work shows the pro-proliferative role of the Ca<jats:sup>2+<\/jats:sup> activated Cl<jats:sup>\u2212<\/jats:sup> channel TMEM16A (anoctamin 1), and demonstrates the essential contribution of TMEM16A to CFTR-dependent Cl<jats:sup>\u2212<\/jats:sup> secretion. The present data demonstrate an increase in intracellular Ca<jats:sup>2+<\/jats:sup> ([Ca<jats:sup>2+<\/jats:sup>]i) signals and Cl<jats:sup>\u2212<\/jats:sup> secretion by TMEM16A, in renal collecting duct principle cells from dog (MDCK) and mouse (M1) as well as primary tubular epithelial cells from PKD1\u2212\/\u2212 knockout mice. M1 organoids proliferated, increased expression of TMEM16A, and secreted Cl<jats:sup>\u2212<\/jats:sup> upon knockdown of endogenous polycystin 1 or 2 (PKD1,2), by retroviral transfection with shPKD1 and shPKD2, respectively. Knockdown of PKD1 or PKD2 increased basal intracellular Ca<jats:sup>2+<\/jats:sup> levels and enhanced purinergic Ca<jats:sup>2+<\/jats:sup> release from endoplasmic reticulum. In contrast, ryanodine receptors were found not to be expressed in mouse renal epithelial cells\u00a0and caffeine had no effects on [Ca<jats:sup>2+<\/jats:sup>]i. Ca<jats:sup>2+<\/jats:sup> signals, proliferation, and Cl<jats:sup>\u2212<\/jats:sup> secretion were largely reduced by knockdown or blockade of TMEM16A. TMEM16A may be\u00a0therefore important for enhanced Ca<jats:sup>2+<\/jats:sup> release from IP<jats:sub>3<\/jats:sub>-sensitive Ca<jats:sup>2+<\/jats:sup> stores in polycystic kidney disease.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Key messages<\/jats:title>\n<jats:p>\u2022 ADPKD leads to continuous decline of renal function by growth of renal cysts.<\/jats:p>\n<jats:p>\u2022 Knockdown of PKD1 or PKD2 increases TMEM16A expression.<\/jats:p>\n<jats:p>\u2022 TMEM16A enhanced intracellular Ca<jats:sup>2+<\/jats:sup> signals, Cl<jats:sup>\u2212<\/jats:sup> secretion, and proliferation.<\/jats:p>\n<jats:p>\u2022 TMEM16A contributes to cyst growth in ADPKD.<\/jats:p>\n<\/jats:sec>","DOI":"10.1007\/s00109-020-01894-y","type":"journal-article","created":{"date-parts":[[2020,3,18]],"date-time":"2020-03-18T00:03:51Z","timestamp":1584489831000},"page":"659-671","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["TMEM16A drives renal cyst growth by augmenting Ca2+ signaling in M1 cells"],"prefix":"10.1007","volume":"98","author":[{"given":"Ines","family":"Cabrita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Buchholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainer","family":"Schreiber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Kunzelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,3,18]]},"reference":[{"key":"1894_CR1","doi-asserted-by":"publisher","unstructured":"Ma M, Gallagher AR, Somlo S (2017) Ciliary mechanisms of cyst formation in polycystic kidney disease. 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