SGLT2 inhibition protects kidney function by SAM-dependent epigenetic repression of inflammatory genes under metabolic stress
Clinically, blockade of renal glucose resorption by sodium-glucose cotransporter 2 (SGLT2) inhibitors slows progression of kidney disease, yet the underlying mechanisms are not fully understood. We hypothesized that altered renal metabolites underlie observed kidney protection when SGLT2 function is lost. S-adenosylmethionine (SAM) levels were increased in kidneys from mice lacking SGLT2 function on a diabetogenic high-fat diet (SPHFD) compared with WT mice fed HFD. Elevated SAM in SPHFD was associated with improved kidney function and decreased expression of NF-κB pathway-related genes. Injured proximal tubular cells that emerged under HFD conditions in WT mice and humans consistently showed reduction in expression of the SAM synthetase Mat2a/MAT2A, while MAT2A inhibition, which reduces SAM production, abrogated kidney protection in SPHFD mice. Histone H3 lysine 27 (H3K27) repressive trimethylation of NF-κB-related genes was increased in SPHFD, consistent with SAM's role as a methyl donor. Our data support a model whereby SGLT2 loss enhances SAM levels within the kidney, leading to epigenetic repression of inflammatory genes and kidney protection under metabolic stress.
Authors
- Margaret E. Fain
- Biliana Marcheva (ORCID: https://orcid.org/0000-0001-8697-2625)
- Yuki Aoi (ORCID: https://orcid.org/0000-0002-0252-9536)
- Joseph T. Bass (ORCID: https://orcid.org/0000-0002-1602-8601)
- Ali Shilatifard (ORCID: https://orcid.org/0000-0002-7490-2854)
- Benjamin C. Howard (ORCID: https://orcid.org/0000-0002-8858-253X)
- Susan E. Quaggin (ORCID: https://orcid.org/0000-0002-3706-5727)
- Hyewon Kong (ORCID: https://orcid.org/0000-0002-6433-9009)
- Zachary L. Sebo (ORCID: https://orcid.org/0000-0003-2495-9083)
- Hiroshi Maekawa (ORCID: https://orcid.org/0000-0002-1104-5197)
- Navdeep S. Chandel (ORCID: https://orcid.org/0000-0001-7208-3886)
- Gregers Rom Andersen (ORCID: https://orcid.org/0000-0001-6292-3319)
- Peng Gao (ORCID: https://orcid.org/0000-0002-9991-6064)
- Dorian Kaminski
- Ram Prosad Chakrabarty (ORCID: https://orcid.org/0000-0002-5425-6306)
- Pinelopi P. Kapitsinou (ORCID: https://orcid.org/0000-0002-6953-0988)
- Yalu Zhou
Institutions
- Northwestern University (US)
- Laboratory of Molecular Genetics (PL)
- Renal Research Institute (US)
- Hypertension Institute (US)
- Institute of Molecular Medicine (IN)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-09-30
- DOI
- https://doi.org/10.1172/jci188933
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00