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Nuclear factor erythroid\u2010related factor 2 (Nrf2) is a master regulator of antioxidant and detoxification pathways and provides cellular protection against oxidative stress. This study aimed to examine the antioxidant effects of linagliptin, a dipeptidyl peptidase\u20104 inhibitor, on DN using streptozotocin (STZ)\u2010induced diabetic Nrf2 knockout (Nrf2KO) mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Six\u2010week\u2010old male Nrf2KO mice and their wild\u2010type (WT) littermates were intraperitoneally injected with STZ (55\u2009mg\/kg) for five consecutive days to induce diabetes (DM) and\/or treated with linagliptin (10\u2009mg\/kg\/day) for 8\u2009weeks. We also investigated the effects of linagliptin and high glucose concentrations on Nrf2\u2010mediated signaling in human renal proximal tubular epithelial cells (HRPTECs) using a NRF2\u2010specific siRNA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Despite the lack of effect on the pathological changes and higher blood glucose levels, linagliptin reduced urinary albuminuria in diabetic mice. Interestingly, linagliptin increased the expression of NADP(H): quinone oxidoreductase\u20101 (NQO1) and LRP2 (megalin) in renal proximal tubular cells of WT and Nrf2KO mice, and these effects were accompanied by the activation of the AKT pathway. Linagliptin increased the expression of\n                      <jats:italic>LRP2<\/jats:italic>\n                      under high glucose conditions through a mechanism independent of NRF2. Finally, an AKT siRNA abolished the stimulatory effects of linagliptin on\n                      <jats:italic>LRP2<\/jats:italic>\n                      expression in HRPTECs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results suggested that linagliptin reduced albuminuria in individuals with DN in an NRF2\u2010independent manner and might exert its effects by upregulating LRP2 expression via the AKT pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jdi.70454","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:52:56Z","timestamp":1790347976000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Linagliptin increases the expression of\n                    <scp>LRP2<\/scp>\n                    independent of Nrf2 in streptozotocin\u2010induced diabetic mice"],"prefix":"10.1111","author":[{"given":"Suratsawadee","family":"Promsuwan","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Metabolism and Rheumatology, Department of Medicine Asahikawa Medical University  Asahikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-7817","authenticated-orcid":false,"given":"Yumi","family":"Takiyama","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Rheumatology, Department of Medicine Asahikawa Medical University  Asahikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Takiyama","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Metabolism and Rheumatology, Department of Medicine Asahikawa Medical University  Asahikawa 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