Omeprazole attenuates cisplatin-induced kidney injury through suppression of the TLR4/NF-κB/NLRP3 signaling pathway.

Renal toxicity is the primary factor that limits clinical use of cisplatin (CP). A previous study showed that omeprazole (OME) protected against CP-induced toxicity in human renal tubular HK-2 cells and rat kidneys. However, the protective mechanisms of OME have not been characterized. We evaluated the ability of OME to inhibit CP-induced inflammation, and characterized the pathways responsible for this effect. Rats were randomly divided into five groups (n = 10/group). The OME groups were intraperitoneally injected with 1.8 or 3.6 mg OME /kg body weight once daily for 5 days. One hour after final administration of vehicle or OME, all rats (except those in control group and OME alone group) were intraperitoneally injected with 15 mg/kg CP. Twenty-four hours after CP injection, the surgery was applied. The time points and dosing of OME and CP were calculated based on previous studies and the therapeutic dose for patients. Omeprazole attenuated CP-induced apoptosis and damage in vivo and in vitro, as evidenced by increased cell viability and prevention of structural damage. Omeprazole ameliorated CP-induced renal injury through inhibition of NF-κB activation and IκBα degradation, and down-regulation of toll-like receptor 4 (TLR4) and Nod-like receptor protein 3 (NLRP3). Lipopolysaccharide, a TLR4 agonist, was used to verify this mechanism. The results indicated that OME inhibited CP-induced expression of inflammatory proteins, and this effect was blunted by co-treatment with LPS in HK-2 cells. These findings suggested that the protective effects of OME against CP-induced kidney damage may occur through inhibition of the TLR4/NF-κB/NLRP3 signaling pathway. This study provided evidence that OME may be a promising agent to inhibit CP-induced nephrotoxicity.