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Purinergic Signal. 2016 Dec;12(4):687-695. Epub 2016 Aug 26.

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells.

Author information

1
Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.
2
Department of Physiology, University of Regensburg, 93053, Regensburg, Germany.
3
Department of Human Genetics, Leiden University Medical Center, Leiden, RC, 2300, The Netherlands.
4
Department of Biomedicine, Physiology, Aarhus University, 8000, Aarhus C, Denmark.
5
Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany. Bjoern.Buchholz@uk-erlangen.de.

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.

KEYWORDS:

ATP; Chloride secretion; Cyst growth; HIF-1α; Hypoxia; P2Y2R; Polycystic kidney disease

PMID:
27565965
PMCID:
PMC5124009
[Available on 2017-02-26]
DOI:
10.1007/s11302-016-9532-5
[Indexed for MEDLINE]
Free PMC Article

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