{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:48:12Z","timestamp":1791233292736,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2021,8,10]],"date-time":"2021-08-10T00:00:00Z","timestamp":1628553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003710","name":"Korea Health Industry Development Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003710","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To evaluate whether sodium\u2010glucose cotransporter\u20102 (SGLT2) inhibition reduces cellular senescence in the kidney and to investigate the molecular pathways involved in the renoprotective effect.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>\n                      Dapagliflozin (1\u00a0mg\/kg), glimepiride (2.5\u00a0mg\/kg) or vehicle was administered daily via oral gavage for 8\u2009weeks in db\/db mice. Expression levels of ageing marker genes (p21, p16, and p53) and oxidative stress were measured in the kidney using real\u2010time RT\u2010PCR, immunohistochemistry, and Western blot analysis. For in vitro analysis, HK\u20102 cells, a human renal tubular epithelial cell line, were pretreated with H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      to induce cellular senescence, and the levels of ageing markers were measured after treatment with \u03b2\u2010hydroxybutyrate (\u03b2\u2010HB) or NRF2\u2010specific siRNA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Expression levels of ageing marker genes (p21, p16 and p53) and senescence\u2010associated secretory phenotypes of the kidney were increased in the vehicle\u2010treated db\/db (db\/db\u2009+\u2009vehicle) group compared with the db\/+ group, and this increase was markedly reversed in the dapagliflozin\u2010treated db\/db (db\/db\u2009+\u2009SGLT2 inhibitor) group, but not in the glimepiride\u2010treated db\/db (db\/db\u2009+\u2009sulphonylurea [SU]) group. In the kidneys of mice in the db\/db\u2009+\u2009SGLT2 inhibitor group, oxidative stress and DNA damage were also reduced compared with those of mice in the db\/db\u2009+\u2009vehicle and db\/db\u2009+\u2009SU groups. Dapagliflozin increased plasma \u03b2\u2010HB, which reduced H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      \u2010induced DNA damage and senescence in HK\u20102 cells. \u03b2\u2010HB\u2010induced NRF2 nuclear translocation mediated anti\u2010senescent effects by inducing antioxidant pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Dapagliflozin prevented the progression of diabetic kidney disease by inhibiting cellular senescence and oxidative stress via ketone\u2010induced NRF2 activation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.14503","type":"journal-article","created":{"date-parts":[[2021,7,28]],"date-time":"2021-07-28T06:27:07Z","timestamp":1627453627000},"page":"2561-2571","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":110,"title":["<scp>Sodium\u2010glucose cotransporter\u20102<\/scp>\n                    inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body\u2010induced\n                    <scp>NRF2<\/scp>\n                    activation"],"prefix":"10.1111","volume":"23","author":[{"given":"Mi Na","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Translational Medicine Seoul National University College of Medicine  Seoul South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1897-0905","authenticated-orcid":false,"given":"Joon Ho","family":"Moon","sequence":"additional","affiliation":[{"name":"Department 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