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

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. [Display omitted] •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 SGLT2 inhibitors have been shown to offer potent renoprotection against diabetic kidney disease. But the mechanism for this effect has been unclear. Here, Tomita et al. report that the drugs promote elevation of ketone bodies, which subsequently inhibit mTORC1 in the proximal renal tubules, explaining their protective effects on this organ.