title: P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells.
abstract: Polycystic kidney diseases are characterized by numerous renal cysts that continuously enlarge resulting in compression of intact nephrons and tissue hypoxia. Recently, we have shown that hypoxia-inducible factor (HIF)-1α promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calcium-activated chloride secretion. Here, we report that HIF-1α directly activates expression of the purinergic receptor P2Y2R in human primary renal tubular cells. In addition, we found that P2Y2R is highly expressed in cyst-lining cells of human ADPKD kidneys as well as PKD1 orthologous mouse kidneys. Knockdown of P2Y2R in renal collecting duct cells inhibited calcium-dependent chloride secretion in Ussing chamber analyses. In line with these findings, knockdown of P2Y2R retarded cyst expansion in vitro and prevented ATP- and HIF-1α-dependent cyst growth. In conclusion, P2Y2R mediates ATP-dependent cyst growth and is transcriptionally regulated by HIF-1α. These findings provide further mechanistic evidence on how hypoxia promotes cyst growth.
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
authors: Andre
authors: A
authors: Kraus
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
authors: Steffen
authors: S
authors: Grampp
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
authors: Margarete
authors: M
authors: Goppelt-Struebe
authors: Department of Physiology, University of Regensburg, 93053, Regensburg, Germany.
authors: Rainer
authors: R
authors: Schreiber
authors: Department of Physiology, University of Regensburg, 93053, Regensburg, Germany.
authors: Karl
authors: K
authors: Kunzelmann
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, RC, 2300, The Netherlands.
authors: Dorien J M
authors: DJ
authors: Peters
authors: Department of Biomedicine, Physiology, Aarhus University, 8000, Aarhus C, Denmark.
authors: Jens
authors: J
authors: Leipziger
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
authors: Gunnar
authors: G
authors: Schley
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
authors: Johannes
authors: J
authors: Schödel
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
authors: Kai-Uwe
authors: KU
authors: Eckardt
authors: Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany. Bjoern.Buchholz@uk-erlangen.de.
authors: Bjoern
authors: 0000-0003-3730-5425
authors: B
authors: Buchholz
mesh_terms: D000818:Animals; D003560:Cysts / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C546385:P2RY2 protein, human; D058473:Receptors, Purinergic P2Y2
keywords: ATP; Chloride secretion; Cyst growth; HIF-1α; Hypoxia; P2Y2R; Polycystic kidney disease