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Sci Rep. 2019 Jul 8;9(1):9887. doi: 10.1038/s41598-019-46402-6.

Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death.

Author information

1
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.
2
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan. eijiro.yamada@gunma-u.ac.jp.
3
Division of Biomedical Sciences, Warwick Medical School, Coventry, West Midlands, United Kingdom.
4
Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Tochigii, Japan.
5
Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan.

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.

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