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Glucose promotes secretion-dependent renal cyst growth

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Abstract

Polycystic kidney diseases are characterized by the development of numerous bilateral renal cysts that continuously enlarge resulting in a decline of kidney function due to compression of intact nephrons. Cyst growth is driven by transepithelial chloride secretion which depends on both intracellular cAMP and calcium. Mechanisms that are involved in the regulation of the underlying secretory pathways remain incompletely understood. Here we show that glucose concentration has a strong impact on cyst growth of renal tubular cells within a collagen matrix as well as in embryonic kidneys deficient or competent for Pkd1. Glucose-dependent cyst growth correlates with the transcriptional induction of the calcium-activated chloride channel anoctamin 1 (ANO1) and its increased expression in the apical membrane of cyst-forming cells. Inhibition of ANO1 with the specific inhibitor CaCCinh-AO1 significantly decreases glucose-dependent cyst growth in both models. Ussing chamber analyses revealed increased apical chloride secretion of renal tubular cells upon exposure to high glucose medium which can also be inhibited by the use of CaCCinh-AO1. These data suggest that glycemic control may help to reduce renal cyst growth in patients with polycystic kidney disease.

Key message

  • Renal cyst growth depends on glucose concentration in two in vitro cyst models.

  • High glucose leads to upregulation of the calcium-activated chloride channel ANO1.

  • High glucose promotes calcium-activated chloride secretion via ANO1.

  • Glucose-dependent secretion can be inhibited by a specific inhibitor of ANO1.

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Acknowledgments

We thank Barbara Teschemacher for excellent technical support. BB was supported by the Deutsche Forschungsgemeinschaft (DFG BU2918/2-1), Else-Kroener-Fresenius Stiftung (2013_A299), the Bayerische Forschungsallianz (BayIntAn_FAU_2014_134), and the Center for Kidney and Blood Pressure Research Regensburg-Erlangen-Nuremberg (REN). GS was supported by the ELAN-Fond of the University of Erlangen-Nürnberg and REN. RS and KK were supported by SFB699 A7/A12. The present work was performed by AK in fulfillment of the requirements for obtaining the degree “Dr. rer. nat.”

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The authors state no conflict of interest.

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Authors and Affiliations

  1. Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany

    Andre Kraus, Gunnar Schley, Kai-Uwe Eckardt & Bjoern Buchholz

  2. Department of Physiology, University of Regensburg, 93053, Regensburg, Germany

    Karl Kunzelmann & Rainer Schreiber

  3. Department of Human Genetics, Leiden University Medical Centre, 2333 ZA, Leiden, Netherlands

    Dorien J. M. Peters

  4. Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, 91054, Erlangen, Germany

    Ruth Stadler

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  1. Andre Kraus
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Correspondence to Bjoern Buchholz.

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Kraus, A., Schley, G., Kunzelmann, K. et al. Glucose promotes secretion-dependent renal cyst growth. J Mol Med 94, 107–117 (2016). https://doi.org/10.1007/s00109-015-1337-4

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  • DOI: https://doi.org/10.1007/s00109-015-1337-4

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