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Changes in Clock Genes Expression in Esophagus in Rat Reflux Esophagitis

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Abstract

Background

Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Clock genes harmonize circadian rhythms by their periodic expression and regulate several physiological functions. However, the association between clock genes and GERD is still unknown.

Aims

We investigated whether reflux esophagitis affects circadian variability of clock genes in the esophagus and other organs using a rat reflux esophagitis model.

Methods

Reflux esophagitis was induced in 7-week-old male Wistar rats. Sham-operated rats were used as controls. Rats were killed at 09:00 (light period) and 21:00 (dark period) 3 days (acute phase) and 21 days (chronic phase) after induction of esophagitis. The expression levels of clock gene mRNAs such as Per1, Per2, Per3, Cry1, Cry2, Arntl, and Clock in the esophagus were investigated by qPCR. Arntl expression was examined in stomach, small intestine, colon, and liver tissues. Serum melatonin and IL-6 levels were measured by ELISA.

Results

Histological examination of reflux esophagitis mainly revealed epithelial defects with marked inflammatory cell infiltration in the acute phase and mucosal thickening with basal cell hyperplasia in the chronic phase. Circadian variability of clock genes, except Cry1, was present in the normal esophagus and was completely disrupted in reflux esophagitis during the acute phase. The circadian variability of Per2, Per3, and Arntl returned to normal, but disruption of Per1, Cry2, and Clock was present in the chronic phase. Disruption of circadian variability of Arntl was observed in the esophagus, as well as in the stomach, small intestine, and liver tissues in reflux esophagitis during the acute phase. There were no significant differences in serum melatonin and IL-6 levels between control and reflux esophagitis animals in both acute and chronic phases.

Conclusions

Disruption to circadian variability of clock genes may play a role in the pathogenesis of GERD.

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Acknowledgments

We thank Emi Yoshioka for her technical assistance.

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Authors and Affiliations

  1. Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan

    Atsushi Hashimoto, Risa Uemura, Akinari Sawada, Yuji Nadatani, Koji Otani, Shuhei Hosomi, Yasuaki Nagami, Fumio Tanaka, Noriko Kamata, Koichi Taira, Hirokazu Yamagami, Tetsuya Tanigawa, Toshio Watanabe & Yasuhiro Fujiwara

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  1. Atsushi Hashimoto
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  2. Risa Uemura
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Contributions

A.H. and Y.F. involved in study concept and design. A.H., R.U., A.S., and Y.F. helped in data acquisition. A.H. and Y.F. involved in analysis and interpretation of data. A.H. drafted the manuscript. A.H., R.U., A.S., Y.N., K.O., K.T., S.H., Y.N., F.T., N.K., H.Y., T.T., T.W., and Y.F. involved in the critical revision of the manuscript for important intellectual content and approval of the final version.

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Correspondence to Yasuhiro Fujiwara.

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Hashimoto, A., Uemura, R., Sawada, A. et al. Changes in Clock Genes Expression in Esophagus in Rat Reflux Esophagitis. Dig Dis Sci 64, 2132–2139 (2019). https://doi.org/10.1007/s10620-019-05546-1

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