title: The enteric nervous system of P2Y13 receptor null mice is resistant against high-fat-diet- and palmitic-acid-induced neuronal loss.
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.
authors: Department of Experimental Medical Science, Lund University, Sölvegatan 19, Lund, BMC B11, SE-22184, Sweden, ulrikke.voss@med.lu.se.
authors: Ulrikke
authors: U
authors: Voss
authors: Michelle Foldschak
authors: MF
authors: Turesson
authors: Bernard
authors: B
authors: Robaye
authors: Jean-Marie
authors: JM
authors: Boeynaems
authors: Björn
authors: B
authors: Olde
authors: David
authors: D
authors: Erlinge
authors: Eva
authors: E
authors: Ekblad
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D017615:Enteric Nervous System / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009197:Myenteric Plexus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D019308:Palmitic Acid / Q000633:toxicity*; D018048:Receptors, Purinergic P2 / Q000172:deficiency*
chemical_list: C486689:P2ry13 protein, mouse; D018048:Receptors, Purinergic P2; D019308:Palmitic Acid