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ER-stress caused by accumulated intracistanal granules activates autophagy through a different signal pathway from unfolded protein response in exocrine pancreas cells of rats exposed to fluoride

  • Organ Toxicity and Mechanisms
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Abstract

In rat exocrine pancreas cells, fluoride treatment causes autophagy resulting from intracisternal granule accumulation. Excessive autophagy might promote a type of programmed cell death different from apoptosis. To clarify how fluoride-induced autophagy and subsequent cell death occurs, we investigated morphological and biochemical changes in exocrine pancreas cells of rats subcutaneously injected with NaF saline solution at 20 mg/kg dose twice daily for 4 days. Intracisternal granule, excessive autophagy and ribosomal degranulation were observed in fluoride-exposed cells, occasionally with necrotic changes. Fluoride-induced rER-stress increased eIF-2α phosphorylation and CHOP expression, but did not affect GRP78. Spliced XBP-1 expression was decreased in damaged cells. These findings indicate that rER-stress by intracisternal granule accumulation lead to autophagy in exocrine pancreas cells without UPR, suggesting that signal process of autophagy differs from that of UPR-apoptosis. It is likely that intense degranulation is a turning point that damaged cells change over from autophagy, cell-protective process, to cell-death process.

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Authors and Affiliations

  1. Laboratory of Toxicology, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku, Sakai, 599-8531, Japan

    Mie Ito, Hiroshi Nakagawa & Saburo Matsuo

  2. Laboratory of Laboratory Animal Science, Course of Veterinary Science, Graduate School of Life and Environmental Biosciences, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku, Sakai, 599-8531, Japan

    Toshiya Okada

  3. Department of Microbiology and Infections Diseases, Toho University School of Medicine, Omori-nishi 5-21-16, Tokyo, 143-8540, Japan

    Syuichi Miyazaki

Authors
  1. Mie Ito
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  2. Hiroshi Nakagawa
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  3. Toshiya Okada
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  4. Syuichi Miyazaki
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  5. Saburo Matsuo
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Corresponding author

Correspondence to Saburo Matsuo.

Additional information

Ire1/XBP-1 is not activated in ER-induced autophagy.

The first and second authors contributed equally to this study.

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Ito, M., Nakagawa, H., Okada, T. et al. ER-stress caused by accumulated intracistanal granules activates autophagy through a different signal pathway from unfolded protein response in exocrine pancreas cells of rats exposed to fluoride. Arch Toxicol 83, 151–159 (2009). https://doi.org/10.1007/s00204-008-0341-7

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  • DOI: https://doi.org/10.1007/s00204-008-0341-7

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