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Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death
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Shibusawa, Ryo, Yamada, Eijiro, Okada, Shuichi, Nakajima, Yasuyo, Bastie, Claire C., Maeshima, A., Kaira, K. and Yamada, Masanobu (2019) Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death. Scientific Reports, 9 (1). 9887 . doi:10.1038/s41598-019-46402-6
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Official URL: https://doi.org/10.1038/s41598-019-46402-6
Abstract
The new type 2 diabetes drug, dapagliflozin, reduces blood glucose levels and body weight by inhibiting sodium glucose transporter 2 (SGLT2) in proximal tubular cells. SGLT2 inhibitors might modulate glucose influx into renal tubular cells, thereby regulating the metabolic conditions that cause endoplasmic reticulum (ER) stress in the cells. In this study, we examined the effect of dapagliflozin on ER stress in the HK-2 proximal tubular cell line and in the kidney of db/db mice to characterise its function in diabetic nephropathy (DN). We found that dapagliflozin regulated ER stress-mediated apoptosis in vitro and in vivo. Only the elf2α-ATF4-CHOP pathway was regulated under these conditions. Notably, the drug rescued C2 ceramide-induced ER stress-mediated apoptosis and ER stress-mediated apoptosis, which might occur in DN, in db/db mice. Our study shows a novel role for dapagliflozin as an inhibitor of ER stress and suggests that dapagliflozin might be useful for the prevention of DN.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > Q Science (General) R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine Faculty of Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Non-insulin-dependent diabetes , Endoplasmic reticulum -- Effect of stress on, Diabetic neuropathies, Nerves, Peripheral -- Diseases, Protein folding | ||||||||
| Journal or Publication Title: | Scientific Reports | ||||||||
| Publisher: | Nature Publishing Group | ||||||||
| ISSN: | 2045-2322 | ||||||||
| Official Date: | 8 July 2019 | ||||||||
| Dates: |
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| Date of first compliant deposit: | 11 July 2019 | ||||||||
| Volume: | 9 | ||||||||
| Number: | 1 | ||||||||
| Article Number: | 9887 | ||||||||
| DOI: | 10.1038/s41598-019-46402-6 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access | ||||||||
| Open Access Version: |
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