ArticleThe Journal of clinical investigation2025
SGLT2 inhibition protects kidney function by SAM-dependent epigenetic repression of inflammatory genes under metabolic stress.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Amino acid homeostasis in the kidney: Physiological roles and pathological dysregulation.Physiological reports · 2026Review
- Glycolytic lactylation modulates cell death decisions in diabetic kidney disease: Metabolic‑epigenetic interplay between ferroptosis and autophagy in fibrotic remodeling (Review).International journal of molecular medicine · 2026Review
- Chronic Kidney Disease in Metabolic Disease: Regulation of SGLT2 and Transcriptomic-Epigenetic Effects of Its Pharmacological Inhibition.International journal of molecular sciences · 2026Review
- Life in the fast lane: Functional consequences of male-female dynamic differences in the renal auto-regulation of flow.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
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.
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