Dapagliflozin rescues endoplasmic reticulum stress-mediated cell death

Area of Science:

• Nephrology
• Endocrinology
• Molecular Biology

Background:

• Sodium-glucose transporter 2 (SGLT2) inhibitors, like dapagliflozin, lower blood glucose and body weight.
• SGLT2 inhibitors may influence glucose transport in renal tubular cells, impacting endoplasmic reticulum (ER) stress.
• Diabetic nephropathy (DN) is associated with ER stress in kidney cells.

Purpose of the Study:

• To investigate the effect of dapagliflozin on ER stress in proximal tubular cells (HK-2 cell line) and in the kidneys of db/db mice.
• To characterize the role of dapagliflozin in diabetic nephropathy (DN) concerning ER stress pathways.

Main Methods:

• Utilized the HK-2 proximal tubular cell line for in vitro studies.
• Employed db/db mice model to assess in vivo effects on kidney tissue.
• Focused on the elf2α-ATF4-CHOP pathway in response to dapagliflozin treatment.

Main Results:

• Dapagliflozin demonstrated regulation of ER stress-mediated apoptosis both in vitro and in vivo.
• The elf2α-ATF4-CHOP pathway was identified as the specific pathway modulated by dapagliflozin.
• Dapagliflozin successfully rescued C2 ceramide-induced ER stress-mediated apoptosis in db/db mice.

Conclusions:

• Dapagliflozin exhibits a novel inhibitory effect on ER stress.
• The drug's ability to mitigate ER stress suggests a potential therapeutic role in preventing diabetic nephropathy (DN).
• Targeting ER stress pathways may be a key mechanism for dapagliflozin in managing DN.