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This project was designed to determine the potential role of USP15 in mediating high glucose (HG)\u2010induced podocyte injury, a key event in the pathogenesis of diabetic nephropathy. We found that USP15 levels were elevated in podocytes after HG stimulation. Inhibition of USP15 led to decreases in HG\u2010evoked apoptosis, oxidative stress, and inflammation in podocytes. Further investigation showed that inhibition of USP15 enhanced the activation of NF\u2010E2\u2010related factor 2 (Nrf2) and expression of Nrf2 target genes in HG\u2010simulated podocytes. Moreover, depletion of Kelch\u2010like ECH\u2010associated protein 1 (Keap1) diminished the regulatory effect of USP15 inhibition on Nrf2 activation. In addition, Nrf2 suppression reversed USP15\u2010inhibition\u2010induced protective effects in HG\u2010injured podocytes. Taken together, these data indicate that USP15 inhibition protects podocytes from HG\u2010induced injury by enhancing Nrf2 activation via Keap1.<\/jats:p>","DOI":"10.1002\/tox.23441","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T07:40:42Z","timestamp":1640072442000},"page":"765-775","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Inhibition of<scp>USP15<\/scp>ameliorates high\u2010glucose\u2010induced oxidative stress and inflammatory injury in podocytes through regulation of the<scp>Keap1\/Nrf2<\/scp>signaling"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2624-5252","authenticated-orcid":false,"given":"Erdi","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Pediatrics The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an 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