Proximal tubule mTORC1 is a central player in the pathophysiology of diabetic nephropathy and its correction by SGLT2 inhibitors
Open accessAbstract
Diabetic kidney disease (DKD) increases the risk for mortality and is the leading cause of end-stage renal disease. Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) attenuates the progression of DKD, especially in patients with advanced kidney disease. Herein, we show that in diabetes, mTORC1 activity is increased in renal proximal tubule cells (RPTCs) along with enhanced tubule-interstitial fibrosis; this is prevented by SGLT2i. Constitutive activation of mTORC1 in RPTCs induces renal fibrosis and failure and abolishes the renal-protective effects of SGLT2i in diabetes. On the contrary, partial inhibition of mTORC1 in RPTCs prevents fibrosis and the decline in renal function. Stimulation of mTORC1 in RPTCs turns on a pro-fibrotic program in the renal cortex, whereas its inhibition in diabetes reverses the alterations in gene expression. We suggest that RPTC mTORC1 is a critical node that mediates kidney dysfunction in diabetes and the protective effects of SGLT2i by regulating fibrogenesis.
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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 Kogot-Levin et al., 2020
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A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors
Sen, T., & Heerspink, H. J. L. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.02.016 · Cited by 161 · see citing works
- Authors
- Kogot-Levin, A., Hinden, L., Riahi, Y., Israeli, T., Tirosh, B., Cerasi, E., Mizrachi, E. B., Tam, J., Mosenzon, O., & Leibowitz, G.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Hadassah Medical Center (IL)
- Corresponding author
- Leibowitz, Gil
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 32
- Issue
- 4
- Pages
- 107954
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7397516
- OpenAlex
- W3045560007
- Cited by
- 126
- References
- 47
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 26 · 2023: 22 · 2022: 26 · 2021: 16
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- European Research Council
- Israel Science Foundation
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- diabetic nephropathy, mTORC1, proximal tubular epithelial cells, SGLT2 inhibitors, renal fibrosis, tubulointerstitial fibrosis, renal fibrogenesis, end-stage renal disease, renal function decline, gene expression
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Sodium-Glucose Transporter 2 Inhibitors, Animals, Diabetes Mellitus, Type 2, Diabetic Nephropathies, Humans, Hypoglycemic Agents, Kidney, Kidney Failure, Chronic, Kidney Tubules, Proximal, Male, Swine, Mice
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