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This study was carried out to investigate the effect of <jats:italic>Gli2<\/jats:italic>, which was an important transcription effector of Hh signaling, on DU induced nephrotoxicity. To clarify it, CK19 positive tubular epithelial cells specific <jats:italic>Gli2<\/jats:italic> conditional knockout (KO) mice model was exposed to DU, and then histopathological damage and Hh signaling pathway activation was analyzed. Moreover, HEK\u2010293\u2009T cells were exposed to DU with Gant61 or <jats:italic>Gli2<\/jats:italic> overexpression, and cytotoxicity of DU as analyzed. Results showed that DU caused nephrotoxicity accompanied by activation of Hh signaling pathway. Meanwhile, genetic KO of <jats:italic>Gli2<\/jats:italic> reduced DU\u2010induced nephrotoxicity by normalizing biochemical indicators and reducing Hh pathway activation. Pharmacologic inhibition of <jats:italic>Gli1<\/jats:italic>\/2 by Gant61 reduced DU induced cytotoxicity by inhibiting apoptosis, ROS formation and Hh pathway activation. However, overexpression of <jats:italic>Gli2<\/jats:italic> aggravated DU\u2010induced cytotoxicity by increasing the levels of apoptosis and ROS formation. Taken together, these results revealed that Hh signaling negatively regulated DU\u2010inducted nephrotoxicity, and that inhibition of <jats:italic>Gli2<\/jats:italic> might serve as a promising nephroprotective target for DU\u2010induced kidney injury.<\/jats:p>","DOI":"10.1002\/tox.24242","type":"journal-article","created":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T13:25:05Z","timestamp":1711632305000},"page":"3833-3845","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hedgehog pathway negatively regulated depleted uranium\u2010induced nephrotoxicity"],"prefix":"10.1002","volume":"39","author":[{"given":"Xueying","family":"Xie","sequence":"first","affiliation":[{"name":"School of Life and Environmental Sciences Shaoxing University  Shaoxing Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoquan","family":"Fu","sequence":"additional","affiliation":[{"name":"School of Life 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