SGLT2 inhibition attenuates diabetic tubulopathy by suppressing SGK1-mediated pyroptosis

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Diabetic kidney disease (DKD) progression is significantly influenced by diabetic tubulopathy.
• Pyroptosis in renal tubular epithelial cells worsens inflammation and tissue damage in DKD.
• The precise mechanism linking sodium-glucose cotransporter 2 (SGLT2) inhibitors to pyroptosis in DKD remains largely unknown.

Purpose of the Study:

• To investigate the role of SGLT2 in pyroptosis of renal tubular cells in DKD.
• To elucidate the signaling pathways involved in SGLT2-mediated pyroptosis.
• To evaluate the therapeutic potential of targeting the SGLT2/SGK1 axis in DKD.

Main Methods:

• Analysis of renal biopsies from DKD patients, diabetic mice, and high glucose-stimulated HK-2 cells.
• Assessment of pyroptosis markers and SGK1 signaling.
• Evaluation of SGLT2 and SGK1 modulation using knockdown, overexpression, and specific inhibitors (empagliflozin and EMD638683).

Main Results:

• SGLT2 and GSDMD-N were elevated in DKD kidneys, correlating with tubular injury and dysfunction.
• Empagliflozin treatment reduced pyroptosis, tubular injury, and fibrosis in diabetic mice.
• In vitro, SGLT2 inhibition by empagliflozin reversed high glucose-induced SGK1 activation and pyroptosis in HK-2 cells; SGK1 inhibition suppressed pyroptosis and NF-κB activation.

Conclusions:

• SGLT2 exacerbates diabetic tubular injury by promoting SGK1-mediated pyroptosis.
• Targeting the SGLT2/SGK1 pathway effectively alleviates pyroptosis.
• Inhibition of the SGLT2/SGK1 axis presents a potential therapeutic strategy for managing DKD.