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TRPC6 channels modulate the response of pancreatic stellate cells to hypoxia

  • Ion channels, receptors and transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Pancreatic cancer is characterized by a massive fibrosis (desmoplasia), which is primarily caused by activated pancreatic stellate cells (PSCs). This leads to a hypoxic tumor microenvironment further reinforcing the activation of PSCs by stimulating their secretion of growth factors and chemokines. Since many of them elicit their effects via G-protein-coupled receptors (GPCRs), we tested whether TRPC6 channels, effector proteins of many G-protein-coupled receptor pathways, are required for the hypoxic activation of PSCs. Thus far, the function of ion channels in PSCs is virtually unexplored. qPCR revealed TRPC6 channels to be one of the most abundant TRPC channels in primary cultures of murine PSCs. TRPC6 channel function was assessed by comparing PSCs from TRPC6−/− mice and wildtype (wt) littermates. Cell migration, Ca2+ signaling, and cytokine secretion were analyzed as readout for PSC activation. Hypoxia was induced by incubating PSCs for 24 h in 1% O2 or chemically with dimethyloxalylglycine (DMOG). PSCs migrate faster in response to hypoxia. Due to reduced autocrine stimulation, TRPC6−/− PSCs fail to increase their rate of migration to the same level as wt PSCs under hypoxic conditions. This defect could not be overcome by the stimulation with platelet-derived growth factor. In line with these results, calcium influx is increased in wt but not TRPC6−/− PSCs under hypoxia. We conclude that TRPC6 channels of PSCs are major effector proteins in an autocrine stimulation pathway triggered by hypoxia.

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Acknowledgements

This work was supported by the Marie Curie Initial Training Network IonTraC (FP7-PEOPLE-2011-ITN grant agreement no. 289648) and Deutsche Forschungsgemeinschaft, Cells-in-Motion Cluster of Excellence (EXC 1003—CiM), University of Münster, Germany, and DFG SCHW 407/17-1.

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Author notes

  1. Ilya Kovalenko

    Present address: Cancer Center, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI, 48104, USA

Authors and Affiliations

  1. Institute of Physiology II, Westfälische Wilhelms-Universität Münster, Robert-Koch-Str. 27b, 48149, Münster, Germany

    Nikolaj Nielsen, Benedikt Hild, Sandra Schimmelpfennig, Jana Welzig, Sarah Sargin, Otto Lindemann & Albrecht Schwab

  2. Inserm, U-1003, Equipe labellisée par la Ligue Nationale Contre le Cancer, Laboratory of Excellence, Ion Channels Science and Therapeutics, Université Lille 1, Villeneuve-d’Ascq, France

    Kateryna Kondratska & Natalia Prevarskaya

  3. Department of Neurology, Albert-Schweitzer-Campus 1, Building A10, Westfälische Wilhelms-Universität Münster, 48149, Münster, Germany

    Tobias Ruck & Sven G. Meuth

  4. Bayer-Pharma AG, Müllerstr. 178, 13353, Berlin, Germany

    Ilya Kovalenko & Sven Christian

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  1. Nikolaj Nielsen
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Correspondence to Albrecht Schwab.

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Conflicts of Interest

At the time of the project SC and IK were employees of Bayer Pharma AG. It did not impact the study design nor data interpretation. Other authors do not have a conflict of interest.

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Nielsen, N., Kondratska, K., Ruck, T. et al. TRPC6 channels modulate the response of pancreatic stellate cells to hypoxia. Pflugers Arch - Eur J Physiol 469, 1567–1577 (2017). https://doi.org/10.1007/s00424-017-2057-0

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  • DOI: https://doi.org/10.1007/s00424-017-2057-0

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