Omeprazole protects against cisplatin-induced nephrotoxicity by alleviating oxidative stress, inflammation, and transporter-mediated cisplatin accumulation in rats and HK-2 cells.

The present study assessed the therapeutic potential of omeprazole (OME), the most commonly prescribed proton pump inhibitor (PPI) used to treat gastroesophageal hyperacidity, against cisplatin (CP)-induced toxicity in human renal tubular HK-2 cells and rat kidneys. Herein, we observed that exposure of HK-2 cells to OME reversed the injury caused by CP, including enhancing cell viability and alleviating intracellular reactive oxygen species (ROS) generation and membrane damage. Concomitantly, acute exposure of male SD rats to CP induced histopathological changes, which were prevented by co-administration with OME. Inflammation and oxidative stress were inhibited by OME during CP-induced renal injury by increasing the activity of superoxide dismutase, and reducing the levels of malondialdehyde, both in vivo and in vitro. The expression levels of major inflammatory response markers were significantly decreased in HK-2 cells and rat kidneys in response to OME. OME reduced CP cellular uptake through organic cation transporters 2 (OCT2) and the prompt efflux of CP by P-glycoprotein (P-gp), thereby reducing the accumulation of CP in kidney tissue and increasing its serum levels. These data demonstrate that CP-induced kidney damage is positively correlated with its cellular accumulation. Concurrently, OME showed renoprotective effect against CP-induced toxicity in HK-2 cells and rat kidneys, by suppressing oxidative stress and mediating NF-κB-dependent inflammation, apoptosis, and transporter function. As OME is commonly used in combination with CP during chemotherapy treatment, this study highlights the clinical significance of OME in alleviating CP-induced nephrotoxicity.