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The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss

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Abstract

Gastrointestinal symptoms have a major impact on the quality of life and are becoming more prevalent in the western population. The enteric nervous system (ENS) is pivotal in regulating gastrointestinal functions. Purinergic neurotransmission conveys a range of short and long-term cellular effects. This study investigated the role of the ADP-sensitive P2Y13 receptor in lipid-induced enteric neuropathy. Littermate P2Y13 +/+ and P2Y13 −/− mice were fed with either a normal diet (ND) or high-fat diet (HFD) for 6 months. The intestines were analysed for morphological changes as well as neuronal numbers and relative numbers of vasoactive intestinal peptide (VIP)- and neuronal nitric oxide synthase (nNOS)-containing neurons. Primary cultures of myenteric neurons from the small intestine of P2Y13 +/+ or P2Y13 −/− mice were exposed to palmitic acid (PA), the P2Y13 receptor agonist 2meSADP and the antagonist MRS2211. Neuronal survival and relative number of VIP-containing neurons were analysed. In P2Y13 +/+, but not in P2Y13 −/− mice, HFD caused a significant loss of myenteric neurons in both ileum and colon. In colon, the relative numbers of VIP-containing submucous neurons were significantly lower in the P2Y13 −/− mice compared with P2Y13 +/+ mice. The relative numbers of nNOS-containing submucous colonic neurons increased in P2Y13 +/+ HFD mice. HFD also caused ileal mucosal thinning in P2Y13 +/+ and P2Y13 −/− mice, compared to ND fed mice. In vitro PA exposure caused loss of myenteric neurons from P2Y13 +/+ mice while neurons from P2Y13 −/− mice were unaffected. Presence of MRS2211 prevented PA-induced neuronal loss in cultures from P2Y13 +/+ mice. 2meSADP caused no change in survival of cultured neurons. P2Y13 receptor activation is of crucial importance in mediating the HFD- and PA-induced myenteric neuronal loss in mice. In addition, the results indicate a constitutive activation of enteric neuronal apoptosis by way of P2Y13 receptor stimulation.

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Acknowledgments

We thank Anna Themner-Persson for excellent technical assistance.

Funding

This study was supported by Påhlsson foundation, Royal Physiographic Society and Faculty of Medicine, Lund University.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Experimental Medical Science, Lund University, Sölvegatan 19, Lund, BMC B11, SE-22184, Sweden

    Ulrikke Voss, Michelle Foldschak Turesson & Eva Ekblad

  2. Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium

    Bernard Robaye

  3. Department of Laboratory Medicine, Erasme Hospital, Brussels, Belgium

    Jean-Marie Boeynaems

  4. Department of Cardiology, Lund University, Lund, Sweden

    Björn Olde & David Erlinge

Authors
  1. Ulrikke Voss
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  2. Michelle Foldschak Turesson
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  3. Bernard Robaye
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  4. Jean-Marie Boeynaems
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  5. Björn Olde
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  6. David Erlinge
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  7. Eva Ekblad
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Correspondence to Ulrikke Voss.

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Voss, U., Turesson, M.F., Robaye, B. et al. The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss. Purinergic Signalling 10, 455–464 (2014). https://doi.org/10.1007/s11302-014-9408-5

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  • DOI: https://doi.org/10.1007/s11302-014-9408-5

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