title: Anoctamin 1 induces calcium-activated chloride secretion and proliferation of renal cyst-forming epithelial cells.
abstract: Polycystic kidney diseases are characterized by multiple bilateral renal cysts that gradually enlarge and lead to a decline in renal function. Cyst enlargement is driven by transepithelial chloride secretion, stimulated by enhanced levels of cyclic adenosine monophosphate, which activates apical cystic fibrosis transmembrane conductance regulator chloride channels. However, chloride secretion by calcium-dependent chloride channels, activated through stimulation of purinergic receptors, also has a major impact. To identify the molecular basis of calcium-dependent chloride secretion in cyst expansion, we determined the role of anoctamin 1 and 6, two recently discovered calcium-activated chloride channels both of which are expressed in epithelial cells. We found that anoctamin 1, which plays a role in epithelial fluid secretion and proliferation, is strongly expressed in principal-like MDCK cells (PLCs) forming cysts within a collagen matrix, in an embryonic kidney cyst model, and in human autosomal dominant polycystic kidney disease tissue. Knockdown of anoctamin 1 but not anoctamin 6 strongly diminished the calcium-dependent chloride secretion of PLCs. Moreover, two inhibitors of anoctamin ion channels, tannic acid and a more selective inhibitor of anoctamin 1, significantly inhibited PLC cyst growth and cyst enlargement in an embryonic kidney cyst model. Knockdown of ANO1 by morpholino analogs also attenuated embryonic cyst growth. Thus, calcium-activated chloride secretion by anoctamin 1 appears to be a crucial component of renal cyst growth.
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Buchholz
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Faria
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Schley
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Schreiber
authors.affiliation: Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Eckardt
authors.affiliation: Department of Physiology, University of Regensburg, Regensburg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Kunzelmann
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D049109:Cell Proliferation / Q000187:drug effects; D018118:Chloride Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D018450:Disease Progression; D004285:Dogs; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009924:Organ Culture Techniques; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism* / Q000473:pathology; D058913:Purinergic Agonists / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: C476213:ANO1 protein, human; C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D002712:Chlorides; D049990:Membrane Transport Modulators; D009363:Neoplasm Proteins; D058913:Purinergic Agonists