SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition
Open accessAbstract
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.
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Ketone bodies may reduce mTORC1-regulated proximal tubular epithelial cell and podocyte damage by inhibiting hyperactive mTORC1 from a hyper-nutrient state, potentially improving kidney function.
“Furthermore, ketone bodies possibly reduce mechanistic target of rapamycin complex 1 (mTORC1)-regulated proximal tubular epithelial cell and podocyte damage by inhibiting hyperactive mTORC1 due to a hyper-nutrient state, which may ameliorate kidney function (Tomita et al., 2020; Kogot-Levin et al., 2020).”
From A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors (2021) · cites this paper as Tomita et al., 2020
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- Authors
- Tomita, I., Kume, S., Sugahara, S., Osawa, N., Yamahara, K., Yasuda-Yamahara, M., Takeda, N., Chin-Kanasaki, M., Kaneko, T., Mayoux, E., Mark, M., Yanagita, M., Ogita, H., Araki, S.-I., & Maegawa, H.
- Affiliations
- Shiga University of Medical Science (JP)
- Boehringer Ingelheim (Japan) (JP)
- Boehringer Ingelheim (Germany) (DE)
- Kyoto University (JP)
- Corresponding author
- Kume, Shinji
- Maegawa, Hiroshi
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 32
- Issue
- 3
- Pages
- 404-419.e6
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W3045763822
- Cited by
- 376
- References
- 9
- Citations by year
- 2026: 57 · 2025: 68 · 2024: 66 · 2023: 61 · 2022: 62 · 2021: 54 · 2020: 7
- FWCI
- 29.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MSD K.K.
- Shiga University of Medical Science
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Japan Agency for Medical Research and Development
- Takeda Medical Research Foundation
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- SGLT2 inhibition, empagliflozin, diabetic nephropathy, ketone bodies, mTORC1, ketogenesis, HMGCS2, lipolysis, ketolysis, proximal tubule, podocyte injury, proteinuria, 1,3-butanediol, ApoE-deficient mice, db/db mice
- MeSH terms
- Mice, Knockout, ApoE, Mechanistic Target of Rapamycin Complex 1, Sodium-Glucose Transporter 2 Inhibitors, Animals, Diabetic Nephropathies, Female, Ketone Bodies, Male, Mice, Inbred C57BL, Sodium-Glucose Transporter 2, Mice
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