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While glucotoxic stress is recognized as a major contributor to tubular aging, the upstream regulatory mechanisms remain incompletely understood. Here, we investigated the role of C1q\/TNF\u2010related protein 1 (CTRP1) in DKD\u2010associated tubular senescence and its mechanistic link to SGLT2\u2010mediated glucose uptake. We conducted a retrospective observational case\u2013control analysis of human renal biopsy specimens, complemented by mechanistic experiments in NRK\u201052E cells and a high\u2010fat diet\/streptozotocin\/uninephrectomy (HFD\u2013STZ\u2013UNx) rat model. Renal cortical tissues from DKD patients and controls were analyzed via immunohistochemistry and Western blotting. CTRP1 expression increased progressively with DKD severity and was positively correlated with the senescence markers p21 (\n                    <jats:italic>R<\/jats:italic>\n                    \u2009=\u20090.498) and p16 (\n                    <jats:italic>R<\/jats:italic>\n                    \u2009=\u20090.494). Bioinformatic analysis of CTRP1\u2010deficient mice revealed consistent SGLT2 downregulation, which was validated experimentally in NRK\u201052E cells, where CTRP1 overexpression increased SGLT2 expression and glucose uptake, particularly under hyperglycemic conditions. In HFD\/STZ\/UNx\u2010induced DKD rats, dapagliflozin (0.1\u2009mg\/kg\/day) improved metabolic abnormalities and renal dysfunction and attenuated tubular senescence. Dapagliflozin suppressed CTRP1\u2013SGLT2 axis activation, reduced glucose uptake in renal tubular cells, and markedly decreased the proportion of CTRP1\n                    <jats:sup>+<\/jats:sup>\n                    SGLT2\n                    <jats:sup>+<\/jats:sup>\n                    double\u2010positive tubular cells. These findings support the presence of a previously unrecognized CTRP1\u2013SGLT2 signaling axis associated with glucose\u2010mediated tubular senescence in DKD and provide mechanistic insight into SGLT2 inhibitor\u2010mediated renoprotection.\n                  <\/jats:p>","DOI":"10.1096\/fj.202601959r","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T14:51:18Z","timestamp":1784213478000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>SGLT2<\/scp>\n                    Inhibition Attenuates Renal Tubular Senescence by Suppressing\n                    <scp>CTRP1<\/scp>\n                    \u2010Mediated Glucotoxic Stress in Diabetic Kidney Disease"],"prefix":"10.1096","volume":"40","author":[{"given":"Lina","family":"Gu","sequence":"first","affiliation":[{"name":"Department of Nephrology Affiliated Hospital of Nanjing University of Chinese Medicine  Nanjing 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