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Doxepin (DOX) is a tricyclic agent with an inhibitory effect on OCT2. This study aimed to explore the possible mechanisms of the renoprotective role of DOX toward CP-induced nephrotoxicity. Rats were randomly divided into six groups: group 1, control; group 2, CP; groups 3, 4, and 5 were treated with graded doses of DOX (5, 10, and 20 mg\/kg, respectively) intraperitoneally (ip) once daily for 10 consecutive days and group 6 was treated only with DOX (20 mg\/kg). On the seventh day, a single injected dose of CP (10 mg\/kg, ip) was given to the rats in groups 2\u20135. Seventy-two hours after CP injection, rats were sacrificed, and the kidneys were removed for histological and biochemical measurements. DOX ameliorated the CP-induced histopathological alterations. DOX significantly reduced the expression of OCT2, lipid peroxidation marker (MDA), and inflammatory cytokines, including TNF-\u03b1, IL-6, IL-1, IL-2, and IL-1\u03b2, and increased the activity of antioxidant enzymes. In addition, pre- and co-treatment with DOX significantly reduced the CP-mediated apoptotic effect by reducing the renal tissue expression of BAX and caspase-3 levels, upregulating the expression of Bcl-2, and modulating the phosphorylation of PI3K\/Akt signaling cascade. DOX exerts a nephroprotective impact against CP-mediated nephrotoxicity via the inhibition of OCT2, suppression of inflammation, oxidative stress, and apoptotic markers, and modulation of PI3K\/Akt signaling cascade.<\/jats:p>","DOI":"10.1007\/s00210-024-03473-1","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T08:01:42Z","timestamp":1728892902000},"page":"3995-4008","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Doxepin as OCT2 inhibitor ameliorates inflammatory response and modulates PI3K\/Akt signaling associated with cisplatin-induced nephrotoxicity in rats"],"prefix":"10.1007","volume":"398","author":[{"given":"Mariam H.","family":"Fawzy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasser M.","family":"Moustafa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina M.","family":"Khodeer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noha M.","family":"Saeed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norhan M.","family":"El-Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,14]]},"reference":[{"issue":"5","key":"3473_CR1","first-page":"460","volume":"10","author":"AA Azadbakht","year":"2015","unstructured":"Azadbakht AA, Radahmadi M, Javanmard SH et al (2015) The effects of doxepin on stress-induced learning, memory impairments, and TNF-\u03b1 level in the rat hippocampus. 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