Contribution of glutamine synthetase to ammonia-induced apoptosis in gastric mucosal cells

Yuuji Kubota, Katsuaki Kato, Naohiro Dairaku, Tomoyuki Koike, Katsunori Iijima, Akira Imatani, Hitoshi Sekine, Shuichi Ohara, Hiroshi Matsui, Tooru Shimosegawa

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15 Citations (Scopus)

Abstract

Background/Aims: Glutamine synthetase is a key enzyme necessary for ammonia detoxification in the brain, but excessive activation of this enzyme can be cytotoxic to neural cells as a consequence of excessive consumption of ATP and glutamate. The stomach also expresses high levels of glutamine synthetase and this study aimed to investigate a possible pathophysiological role of glutamine synthetase in ammonia-induced gastric mucosal injury. Methods: Normal rat gastric mucosal epithelial (RGM-1) cells were treated with ammonia, and a specific glutamine synthetase inhibitor (methionine sulfoximine) was used to assess the action of glutamine synthetase. Results: Treatment with ammonia induced apoptotic cell death. Increased expression of p21 and Bax, decreased expression of Bcl-2, cytochrome C release from the mitochondria into the cytosol and subsequent activation of caspase-9 and -3 were identified in the cells treated with ammonia, although there was no apparent change in p53 expression. On the other hand, pretreatment with various concentrations of methionine sulfoximine reduced the glutamine synthetase activity in ammonia-treated RGM-1 cells, and prevented the induction of apoptosis and the reduction in intracellular ATP levels in a dose-dependent manner. Conclusions: Our results suggested that the energy exhaustion which resulted from an overload of ammonia to glutamine synthetase may have initiated the apoptotic signaling in gastric mucosal cells.

Original languageEnglish
Pages (from-to)140-148
Number of pages9
JournalDigestion
Volume69
Issue number3
DOIs
Publication statusPublished - 2004

Keywords

  • Ammonia
  • Apoptosis
  • Bax
  • Bcl-2
  • Caspase
  • Glutamine synthetase
  • Methionine sulfoximine
  • Stomach
  • p21

ASJC Scopus subject areas

  • Gastroenterology

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  • Cite this

    Kubota, Y., Kato, K., Dairaku, N., Koike, T., Iijima, K., Imatani, A., Sekine, H., Ohara, S., Matsui, H., & Shimosegawa, T. (2004). Contribution of glutamine synthetase to ammonia-induced apoptosis in gastric mucosal cells. Digestion, 69(3), 140-148. https://doi.org/10.1159/000078152