SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition

Area of Science:

• Nephrology
• Metabolic Diseases
• Pharmacology

Background:

• Diabetic kidney disease (DKD) is a major complication of diabetes, and SGLT2 inhibitors show significant renoprotective effects.
• The precise mechanisms underlying SGLT2 inhibitor-mediated renoprotection in DKD, particularly in non-proteinuric stages, remain incompletely understood.
• Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) is implicated in kidney damage.

Purpose of the Study:

• To elucidate the mechanism by which SGLT2 inhibitors protect against DKD.
• To investigate the role of ketone bodies (KBs) and mTORC1 signaling in DKD pathogenesis and SGLT2 inhibitor efficacy.

Main Methods:

• Utilized high-fat diet-fed ApoE-knockout mice as a model for non-proteinuric DKD.
• Administered empagliflozin and 1,3-butanediol (a KB precursor) to assess effects on renal ATP levels and organ damage.
• Employed gene deletion of Hmgcs2 (a key ketogenesis enzyme) to confirm the role of KBs.
• Investigated the impact of KBs on podocyte damage and proteinuria in diabetic db/db mice.

Main Results:

• In non-proteinuric DKD, damaged proximal tubules exhibited a shift in ATP production from lipolysis to ketolysis due to mTORC1 hyperactivation.
• Empagliflozin increased endogenous KB levels, preventing ATP depletion and organ damage in mice; this effect was abrogated by Hmgcs2 deletion.
• Ketone bodies attenuated mTORC1-associated podocyte injury and proteinuria in both non-proteinuric and proteinuric DKD models.

Conclusions:

• SGLT2 inhibition-associated renoprotection in DKD is mediated by elevated ketone bodies.
• Increased KBs correct mTORC1 hyperactivation, thereby mitigating kidney damage in both non-proteinuric and proteinuric DKD.
• Targeting ketogenesis represents a potential therapeutic strategy for DKD.