Doxepin as OCT2 inhibitor ameliorates inflammatory response and modulates PI3K/Akt signaling associated with cisplatin-induced nephrotoxicity in rats

Organic cationic transporter 2 (OCT2) was identified as the main transporter involved in the accumulation of cisplatin (CP) in the proximal tubular renal cells, resulting in nephrotoxicity. 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 2-5. 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-α, IL-6, IL-1, IL-2, and IL-1β, 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.