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We hypothesized that altered renal metabolites underlie observed kidney protection when SGLT2 function is lost.\n                    <jats:italic>S<\/jats:italic>\n                    -adenosylmethionine (SAM) levels were increased in kidneys from mice lacking SGLT2 function on a diabetogenic high-fat diet (SP\n                    <jats:sup>HFD<\/jats:sup>\n                    ) compared with WT mice fed HFD. Elevated SAM in SP\n                    <jats:sup>HFD<\/jats:sup>\n                    was associated with improved kidney function and decreased expression of NF-\u03baB pathway\u2013related genes. Injured proximal tubular cells that emerged under HFD conditions in WT mice and humans consistently showed reduction in expression of the SAM synthetase\n                    <jats:italic>Mat2a\/MAT2A<\/jats:italic>\n                    , while MAT2A inhibition, which reduces SAM production, abrogated kidney protection in SP\n                    <jats:sup>HFD<\/jats:sup>\n                    mice. Histone H3 lysine 27 (H3K27) repressive trimethylation of NF-\u03baB\u2013related genes was increased in SP\n                    <jats:sup>HFD<\/jats:sup>\n                    , consistent with SAM\u2019s 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.\n                  <\/jats:p>","DOI":"10.1172\/jci188933","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T18:01:01Z","timestamp":1759255261000},"source":"Crossref","is-referenced-by-count":8,"title":["SGLT2 inhibition protects kidney function by SAM-dependent epigenetic repression of inflammatory genes under metabolic stress"],"prefix":"10.1172","volume":"135","author":[{"given":"Hiroshi","family":"Maekawa","sequence":"first","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute,"},{"name":"Division of Nephrology & Hypertension, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute,"},{"name":"Division of Nephrology & Hypertension, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Aoi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, and"},{"name":"Simpson Querrey Institute for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret E.","family":"Fain","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute,"},{"name":"Division of Nephrology & Hypertension, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorian S.","family":"Kaminski","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular & Renal Research Institute,"},{"name":"Division of Nephrology & Hypertension, Department of Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyewon","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Medicine & Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary L.","family":"Sebo","sequence":"additional","affiliation":[{"name":"Department of Medicine & Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram P.","family":"Chakrabarty","sequence":"additional","affiliation":[{"name":"Department of Medicine & Biochemistry and Molecular Genetics, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin C.","family":"Howard","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, and"},{"name":"Simpson Querrey Institute for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Andersen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, and"},{"name":"Simpson Querrey Institute for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biliana","family":"Marcheva","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Molecular Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Gao","sequence":"additional","affiliation":[{"name":"Robert H. 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