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

Kraus A, Grampp S, Goppelt-Strübe M, Schreiber R, Kunzelmann K, Peters DJM, Leipziger J, Schley G, Schoedel J, Eckardt KU, Buchholz B (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Purinergic Signalling Springer Verlag (Germany)

Book Volume: 12

Pages Range: 687-695

Journal Issue: 4

DOI: 10.1007/s11302-016-9532-5

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)-1 alpha promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calcium-activated chloride secretion. Here, we report that HIF-1 alpha 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-1 alpha-dependent cyst growth. In conclusion, P2Y2R mediates ATP-dependent cyst growth and is transcriptionally regulated by HIF-1 alpha. These findings provide further mechanistic evidence on how hypoxia promotes cyst growth.

Authors with CRIS profile

Andre Kraus Department of Medicine 4 – Nephrology and Hypertension Margarete Goppelt-Strübe Department of Medicine 4 – Nephrology and Hypertension Kai-Uwe Eckardt Department of Medicine 4 – Nephrology and Hypertension Björn Buchholz Department of Medicine 4 – Nephrology and Hypertension

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Involved external institutions

Universität Regensburg DE Germany (DE) Leiden University NL Netherlands (NL) Aarhus University DK Denmark (DK)

How to cite

APA:

Kraus, A., Grampp, S., Goppelt-Strübe, M., Schreiber, R., Kunzelmann, K., Peters, D.J.M.,... Buchholz, B. (2016). P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells. Purinergic Signalling, 12(4), 687-695. https://dx.doi.org/10.1007/s11302-016-9532-5

MLA:

Kraus, Andre, et al. "P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells." Purinergic Signalling 12.4 (2016): 687-695.

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