Cell Metabolism
Volume 32, Issue 3, 1 September 2020, Pages 404-419.e6
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Article
SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition

https://doi.org/10.1016/j.cmet.2020.06.020Get rights and content
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Highlights

  • Energy metabolism shifts from lipolysis to ketolysis in damaged kidneys

  • mTORC1 hyperactivation leads to impaired renal lipolysis and subsequent renal damage

  • Ketone body supplementation ameliorates renal damage by blocking mTORC1 signaling

  • SGLT2 inhibitor-mediated renoprotection involves mTORC1 inhibition by ketone bodies

Summary

SGLT2 inhibitors offer strong renoprotection in subjects with diabetic kidney disease (DKD). But the mechanism for such protection is not clear. Here, we report that in damaged proximal tubules of high-fat diet-fed ApoE-knockout mice, a model of non-proteinuric DKD, ATP production shifted from lipolysis to ketolysis dependent due to hyperactivation of the mechanistic target of rapamycin complex 1 (mTORC1). We further found that empagliflozin raised endogenous ketone body (KB) levels, and thus its use or treatment with 1,3-butanediol, a KB precursor, prevented decreases in renal ATP levels and organ damage in the mice. The renoprotective effect of empagliflozin was abolished by gene deletion of Hmgcs2, a rate-limiting enzyme of ketogenesis. Furthermore, KBs attenuated mTORC1-associated podocyte damage and proteinuria in diabetic db/db mice. Our findings show that SGLT2 inhibition-associated renoprotection is mediated by an elevation of KBs that in turn corrects mTORC1 hyperactivation that occurs in non-proteinuric and proteinuric DKD.

Keywords

diabetic kidney disease
atherosclerosis
ketone body
SGLT2 inhibitor
lipolysis
ketolysis
mTORC1
nutrient-sensing signal
renal energy metabolism

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